Triazolopyridinylsulfanyl derivatives as P38 map kinase inhibitors

ABSTRACT

A compound of formula (I), or a pharmaceutical acceptable salt and/or solvate (including hydrate) thereof; 
                         
and the use of a compound of formula (I) in the treatment of a TNF-mediated disease, disorder, or condition, or a p38-mediated disease, disorder, or condition, in particular the allergic and non-allergic airways diseases, more particularly obstructive or inflammatory airways diseases, preferably chronic obstructive pulmonary disease.

This application is a continuation of U.S. patent application Ser. No.11/201,823, filed Aug. 10, 2005, which claims priority to U.S.Provisional Application Nos. 60/606,228, filed Aug. 31, 2004;60/606,256, filed Aug. 31, 2004; and 60/691,559, filed Jun. 17, 2005.

This invention relates to triazolopyridinylsulfanyl derivatives. Moreparticularly, this invention relates topyrazolyl-[(triazolopyridinylsulfanyl)-benzyl]-urea derivatives and toprocesses for the preparation of, intermediates used in the preparationof, compositions containing and the uses of, such derivatives.

The triazolopyridinylsulfanyl derivatives of the present invention areinhibitors of p38 mitogen activated protein kinase (“p38 MAPK”, “p38kinase” or “p38”), particularly p38α kinase, and are inhibitors of tumornecrosis factor (“TNF”) production, particularly TNFα. They have anumber of therapeutic applications, particularly in the treatment ofallergic and non-allergic airways diseases, more particularlyobstructive or inflammatory airways diseases such as chronic obstructivepulmonary disease (“COPD”).

Mitogen activated protein kinases (MAP) constitute a family ofproline-directed serine/threonine kinases that activate their substratesby dual phosphorylation. The kinases are activated by a variety ofsignals, including nutritional and osmotic stress, UV light, growthfactors, endotoxin, and inflammatory cytokines. The p38 MAP kinase groupis a MAP family of various isoforms, including p38α, p38β, and p38γ.These kinases are responsible for phosphorylating and activatingtranscription factors (e.g., ATF2, CHOP, and MEF2C), as well as otherkinases (e.g., MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated bybacterial lipopolysaccharide, physical and chemical stress, andproinflammatory cytokines, including tumor necrosis factor (“TNF”) andinterleukin-1 (“IL-1”). The products of the p38 phosphorylation mediatethe production of inflammatory cytokines, including TNF.

TNF is a cytokine produced primarily by activated monocytes andmacrophages. Excessive or unregulated TNF production (particularlyTNF-α) has been implicated in mediating a number of diseases, and it isbelieved that TNF can cause or contribute to the effects of inflammationin general.

IL-8 is another pro-inflammatory cytokine, which is produced bymononuclear cells, fibroblasts, endothelial cells, and keratinocytes.This cytokine is associated with conditions including inflammation. IL-1is produced by activated monocytes and macrophages, and is involved ininflammatory responses. IL-1 plays a role in many pathophysiologicalresponses, including rheumatoid arthritis, fever, and reduction of boneresorption.

TNF, IL-1, and IL-8 affect a wide variety of cells and tissues, and areimportant inflammatory mediators of a wide variety of conditions.Compounds which inhibit p38 kinase will inhibit IL-1, IL-8, and TNFsynthesis in human monocytes.

P38 kinase inhibitors are well known to the person skilled in the art.J. Med. Chem. 2002, 45, 2994-3008 discloses certain pyrazole ureacompounds as inhibitors of p38 kinase. International patent applicationPCT/IB02/00424 (WO 02/072579) discloses triazolopyridines as inhibitorsof MAP kinases, preferably p38 kinase.

International patent application PCT IB2004/000363 (WO 2004/072072),publication date 26 Aug. 2004, discloses triazolo-pyridines useful asanti-inflammatory compounds for treating certain diseases. This isincorporated by reference in its entirety.

The compounds of the present invention are potentially useful in thetreatment of a wide range of disorders. In addition to the treatment ofobstructive or inflammatory airways diseases, it is believed that thecompounds of the present invention can be used to treat TNF/p38 mediateddiseases such as: asthma, chronic or acute bronchoconstriction,bronchitis, acute lung injury and bronchiectasis, inflammation generally(e.g. inflammatory bowel disease), arthritis, neuroinflammation, pain,fever, fibrotic diseases, pulmonary disorders and diseases (e.g.,hyperoxic alveolar injury), cardiovascular diseases, post-ischemicreperfusion injury and congestive heart failure, cardiomyopathy, stroke,ischemia, reperfusion injury, renal reperfusion injury, brain edema,neurotrauma and brain trauma, neurodegenerative disorders, centralnervous system disorders, liver disease and nephritis, gastrointestinalconditions, ulcerative diseases, ophthalmic diseases, opthalmologicalconditions, glaucoma, acute injury to the eye tissue and ocular traumas,diabetes, diabetic nephropathy, skin-related conditions, myalgias due toinfection, influenza, endotoxic shock, toxic shock syndrome, autoimmunedisease, graft rejection, bone resorption diseases, multiple sclerosis,psoriasis, disorders of the female reproductive system, pathological(but non-malignant) conditions, such as hemaginomas, angiofibroma of thenasopharynx, and avascular necrosis of bone, benign and malignanttumors/neoplasia including cancer, leukaemia, lymphoma, systemic lupuserthrematosis (SLE), angiogenesis including neoplasia, hemorrhage,coagulation, radiation damage, and/or metastasis. Chronic release ofactive TNF can cause cachexia and anorexia, and TNF can be lethal.

TNF has also been implicated in infectious diseases. These include, forexample, malaria, mycobacterial infection and meningitis. These alsoinclude viral infections, such as HIV, influenza virus, and herpesvirus, including herpes simplex virus type-1 (HSV-1), herpes simplexvirus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus(VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), humanherpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies andrhinotracheitis, among others.

The treatment of obstructive or inflammatory airways diseases is apreferred use. All forms of obstructive or inflammatory airways diseasesare potentially treatable with the compounds of the present invention,in particular an obstructive or inflammatory airways disease that is amember selected from the group consisting of chronic eosinophilicpneumonia, COPD, COPD that includes chronic bronchitis, pulmonaryemphysema or dyspnea associated or not associated with COPD, COPD thatis characterized by irreversible, progressive airways obstruction, adultrespiratory distress syndrome (ARDS), exacerbation of airwayshyper-reactivity consequent to other drug therapy and airways diseasethat is associated with pulmonary hypertension.

There is a need to provide new TNF inhibitors/p38 kinase inhibitors thatare good drug candidates. Preferably, the new TNF inhibitors/p38 kinaseinhibitors show good potency, high levels of selectivity over otherrelated protein kinases, have properties particularly suitable forproviding effective treatment via the inhalation route, are suitable forthe treatment of allergic and non-allergic airways diseases(particularly obstructive or inflammatory airways diseases), arenon-toxic and demonstrate few side-effects, have physical propertiessuitable for administration by inhalation, exist in a physical form thatis stable and non-hygroscopic, and/or are easily formulated.

According to one aspect of the present invention, there is provided acompound of formula (I):

or a pharmaceutical acceptable salt and/or solvate (including hydrate)thereof,whereinR¹ is CH₃, S(O)_(p)CH₃, S(O)_(p)CH₂CH₃, CH₂CH₃, H or CH₂S(O)_(p)CH₃;R^(1a) is CH₃ or CH₂CH₃, wherein CH₃ and CH₂CH₃ are each optionallysubstituted with one or more hydroxy substituents;R² is heteroaryl, heterocyclyl, aryl, or carbocyclyl;R³ is heteroaryl, heterocyclyl, aryl, carbocyclyl or R⁷;R⁷ is (C₁-C₆)alkyl (optionally substituted with one or more substituentsindependently selected from OH, halo, NR⁵R⁶, (C₁-C₆)alkoxy,—S(O)_(p)(C₁-C₆)alkyl, CO₂H, CONR⁵R⁶, heteroaryl, heterocyclyl, aryl,carbocyclyl, aryloxy, carbocyclyloxy, heteroaryloxy andheterocyclyloxy);p is 0, 1 or 2;R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl, said(C₁-C₄)alkyl being optionally substituted with one or more substituentsindependently selected from OH and halo,or R⁵ and R⁶, together with the nitrogen to which they are attached forma piperazinyl, piperidinyl, morpholinyl or pyrrolidinyl group, (saidpiperazinyl, piperidinyl, morpholinyl and pyrrolidinyl each beingoptionally substituted by one or more OH)each “aryl” independently means phenyl or naphthyl, said phenyl ornaphthyl being optionally substituted with one or more substituentsindependently selected from halo, —CN, —CO₂H, OH, CONR⁵R⁶, NR⁵R⁶, R⁸ andR⁹, and preferably, said phenyl or naphthyl being optionally substitutedwith one or more substituents independently selected from halo, —CN,—CO₂H, OH, CONR⁵R⁶, R⁸ and R⁹;each R⁸ is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,—CO₂(C₁-C₆)alkyl, —S(O)_(p)(C₁-C₆)alkyl, —CO(C₁-C₆)alkyl and(C₃-C₇)cycloalkyl;each R⁸ is optionally substituted with one or more substituentsindependently selected from:(C₁-C₆)alkoxy (optionally substituted with one or more substituentsindependently selected from OH, halo, CO₂H, CONR⁵R⁶ and NR⁵R⁶),—S(O)_(p)(C₁-C₆)alkyl (optionally substituted with one or moresubstituents independently selected from OH, halo, CO₂H, CONR⁵R⁶ andNR⁵R⁶),OH,halo,NR⁵R⁶,CO₂HCONR⁵R⁶, andR⁹;each R⁹ is heteroaryl², heterocyclyl², aryl², carbocyclyl², aryl²oxy,carbocyclyl²oxy, heteroaryl²oxy or heterocyclyl²oxy;“aryl²”, means phenyl or naphthyl, said phenyl or naphthyl beingoptionally substituted with one or more substituents independentlyselected from halo, —CN, —CO₂H, OH, NR⁵R⁶, and CONR⁵R⁶, and preferably,said phenyl or naphthyl being optionally substituted with one or moresubstituents independently selected from halo, —CN, —CO₂H, OH andCONR⁵R⁶;“carbocyclyl” means a mono or bicyclic, saturated or partiallyunsaturated ring system containing from 3 to 10 ring carbon atoms,optionally substituted with one or more substituents independentlyselected from halo, —CN, —CO₂H, OH, NR⁵R⁶, CONR⁵R⁶, R⁸ and R⁹, andpreferably, optionally substituted with one or more substituentsindependently selected from halo, —CN, —CO₂H, OH, CONR⁵R⁶, R⁸ and R⁹;“carbocyclyl²” means a mono or bicyclic, saturated or partiallyunsaturated ring system containing from 3 to 10 ring carbon atoms,optionally substituted with one or more substituents independentlyselected from halo, —CN, —CO₂H, NR⁵R⁶, OH and CONR⁵R⁶, and preferably,optionally substituted with one or more substituents independentlyselected from halo, —CN, —CO₂H, OH and CONR⁵R⁶,examples of “carbocyclyl” and “carbocyclyl²” are groups such as:indanyl, indenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclohexenyl, cycloheptyl and tetrahydronaphthyl;each “heterocyclyl”, and “heterocyclyl²”, independently, means a 3- to10-membered, saturated or partially unsaturated, mono or bicyclic groupcomprising 1, 2, 3 or 4 ring heteroatoms independently selected from N,O, and S. Examples of “heterocyclyl” and “heterocyclyl²” are groups suchas: tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl,1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl,3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl,1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, dihydroindolyland dihydrobenzofuranyl.each “heteroaryl”, and each “heteroaryl²”, independently, means a 5 to10 membered, mono or bicyclic, aromatic group comprising 1, 2, 3 or 4ring heteroatoms independently selected from N, O, and S (wherein thetotal number of ring S atoms does not exceed 1, and the total number ofring O atoms does not exceed 1), and includes the groups:pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl,1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl,1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl,indolyl, benzimidazolyl, indazolyl, benzotriazolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, purinyl,indolininyl, imidazol[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, pyrrolo[1-2,b]pyridazinyl,imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl,2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl,pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl,pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl,pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl;each “heterocyclyl” and each “heteroaryl” group is, independently,optionally substituted on one or more ring carbon atoms with one or moresubstituents independently selected from halo, —CN, —CO₂H, OH, NR⁵R⁶,CONR⁵R⁶, R⁸ and R⁹, and preferably, optionally substituted on one ormore ring carbon atoms with one or more substituents independentlyselected from halo, —CN, —CO₂H, OH, CONR⁵R⁶, R⁸ and R⁹,and optionally substituted on one or more ring nitrogen atoms with oneor more substituents independently selected from H and (C₁-C₆)alkyl;each “heterocyclyl²” and each “heteroaryl²” group is, independently,optionally substituted on one or more ring carbon atoms with one or moresubstituents independently selected from halo, —CN, —CO₂H, NR⁵R⁶, OH andCONR⁵R⁶, and preferably, optionally substituted on one or more ringcarbon atoms with one or more substituents independently selected fromhalo, —CN, —CO₂H, OH and CONR⁵R⁶, and optionally substituted on one ormore ring nitrogen atoms with one or more substituents independentlyselected from H and (C₁-C₆)alkyl;“alkyl” and “alkoxy” groups, including groups incorporating saidmoieties, may be straight chain or branched where the number of carbonatoms allows. “(C₁-C₄)alkyl” or “(C₁-C₆)alkyl” denotes a straight) chainor branched group containing respectively from 1 to 4 or from 1 to 6carbon atoms. This also applies if they carry substituents or occur assubstituents of other radicals, for example in (C₁-C₆)alkoxy radicals,—CO₂(C₁-C₆)alkyl radicals, —CO(C₁-C₆)alkyl radicals, or—S(O)_(p)(C₁-C₆)alkyl radicals. Examples of suitable (C₁-C₄)alkyl or(C₁-C₆)alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl. Examples of suitable(C₁-C₆)alkoxy radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy,n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy, pentyloxy andhexyloxy.“halogen” or “halo” is taken to mean a halogen atom selected from thegroup consisting of fluorine, chlorine and bromine.

It is to be appreciated that all references herein to “treatment”,“treat” or “treating” include curative, palliative and/or prophylactictreatment.

“compounds of the invention” or “a compound of the invention” as usedherein means compounds, or a compound, of formula (I), or apharmaceutically acceptable salt and/or solvate thereof, and includesall polymorphs and crystal habits thereof, prodrugs and isomers thereof(including optical, geometric and tautomeric isomers), and mixturesthereof, as hereinafter defined and isotopically-labeled compounds offormula I.

It has now been found that the compounds of formula (I) are p38inhibitors/inhibitors of TNF production, are particularly useful for thetreatment of a TNF mediated, and/or p38 mediated, disease, disorder, orcondition, and are particularly suitable for administration via theinhalation route.

In another aspect of the invention there is provided a compound offormula (I), or a pharmaceutically acceptable salt and/or solvate(including hydrate) thereof, wherein

R¹ is CH₃, SCH₃, SCH₂CH₃, CH₂CH₃, H or CH₂SCH₃;

R^(1a) is CH₃ or CH₂CH₃;

and wherein

R², R³, R⁷, p, R⁵, R⁶, “aryl”, R⁸, R⁹, “aryl², “carbocyclyl”,“carbocyclyl², “heterocyclyl”, “heterocyclyl²”, “heteroaryl” and“heteroaryl²”, are all as defined above.

Preferably, R¹ is CH₃, SCH₃, SCH₂CH₃ or CH₂SCH₃, and more preferably R¹is CH₃ or SCH₃.

In an alternative embodiment, preferably R¹ is CH₃, SCH₃, CH₂CH₃ orCH₂SCH₃, and more preferably R¹ is CH₃, CH₂CH₃ or CH₂SCH₃.

Preferably, R^(1a) is CH₃.

Preferably, R² is pyridyl, tetrahydronaphthyl or aryl,

said pyridyl, tetrahydronaphthyl and aryl each being optionallysubstituted with one or more substituents independently selected fromthe group consisting of:

halo,

—CN,

—CO₂H

OH,

CONR⁵R⁶

(C₁-C₆)alkyl (said (C₁-C₆)alkyl being optionally substituted with one ormore substituents independently selected from OH, NR⁵R⁶, aryl² andhalo),

—S(O)_(p)(C₁-C₆)alkyl (said —S(O)_(p)(C₁-C₆)alkyl being optionallysubstituted with one or more substituents independently selected fromOH, aryl² and halo),

(C₁-C₆)alkoxy (said (C₁-C₆)alkoxy being optionally substituted with oneor more substituents independently selected from OH, aryl² and halo),

—CO₂(C₁-C₆)alkyl (said —CO₂(C₁-C₆)alkyl being optionally substitutedwith one or more substituents independently selected from OH, aryl² andhalo),

(C₃-C₇)cycloalkyl (said (C₃-C₇)cycloalkyl being optionally substitutedwith one or more substituents independently selected from OH and halo),

pyridyl, and

aryl²,

More preferably, R² is:

3-pyridyl (optionally substituted with one or more substituentsindependently selected from OH, —S(C₁-C₆)alkyl, (C₁-C₆)alkoxy, CF₃ andhalo), or

phenyl (optionally substituted with one or more substituentsindependently selected from (C₁-C₆)alkyl, OH, —S(C₁-C₆)alkyl,(C₁-C₆)alkoxy, CN, CF₃ and halo).

Yet more preferably, R² is phenyl (optionally substituted with one ormore substituents independently selected from methyl, ethyl, OH, CN,CF₃, Cl, F, —SCH₃ and —OCH₃).

Even more preferably, R² is 3-hydroxyphenyl, 4-hydroxyphenyl, phenyl,3,4-dichlorophenyl, 4-methylphenyl, 3-methoxyphenyl,4-hydroxy-3-methylphenyl, 3-methylphenyl or 4-hydroxy-3-chlorophenyl.

In an alternative embodiment, R² is preferably pyridyl or aryl,

said pyridyl and aryl each being optionally substituted with one or moresubstituents independently selected from the group consisting of:

halo,

—CN,

—CO₂H

OH,

CONR⁵R⁶

(C₁-C₆)alkyl (said (C₁-C₆)alkyl being optionally substituted with one ormore substituents independently selected from OH, NR⁵R⁶ and halo),

(C₁-C₆)alkoxy (said (C₁-C₆)alkoxy being optionally substituted with oneor more substituents independently selected from OH, CO₂H, aryl² andhalo),

More preferably, R² is:

3-pyridyl (optionally substituted with one or more substituentsindependently selected from OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and CF₃), or

phenyl (optionally substituted with one or more substituentsindependently selected from (C₁-C₆)alkyl, OH, —S(C₁-C₆)alkyl (whereinsaid —S(C₁-C₆)alkyl is optionally substituted with OH), (C₁-C₆)alkoxy(wherein said (C₁-C₆)alkoxy is optionally substituted with OH), CN, CF₃and halo).

Even more preferably, R² is phenyl optionally substituted with one ormore substituents independently selected from (C₁-C₄)alkyl, OH,—S(C₁-C₄)alkyl (wherein said —S(C₁-C₄)alkyl is optionally substitutedwith OH), (C₁-C₄)alkoxy (wherein said (C₁-C₄)alkoxy is optionallysubstituted with OH), CN, CF₃ and halo).

Yet more preferably, R² is phenyl (optionally substituted with one ormore substituents independently selected from methyl, ethyl, OH, CN,CF₃, Cl, F and —OCH₂CH₂OH).

Yet even more preferably, R² is phenyl substituted with one or twosubstituents independently selected from OH, Cl, CN, methyl and—OCH₂CH₂OH.

Preferably, when R² is substituted phenyl, the substitution is at the 3-and/or 4-positions of said phenyl.

In another preferred embodiment, when R² is phenyl substituted with ahydroxyethoxy substituent, said hydroxyethoxy substituent is at the 3(meta) position of the phenyl.

In a particularly preferred embodiment of the invention, R² issubstituted phenyl according to any one of the embodiments orpreferences herein, wherein the R² phenyl is substituted with at leastone hydroxy substituent, or at least one hydroxyethoxy substituent, morepreferably at least one hydroxy substituent.

In a preferred embodiment of the invention, R² is phenyl substituted by:

3-chloro and 4-hydroxy, 3-cyano and 4-hydroxy, 3-hydroxy, 4-hydroxy,3-hydroxyethoxy, 3-hydroxy and 4-chloro, or 3-hydroxy and 4-cyano.

In another embodiment, R² is preferably, 3-hydroxyphenyl,4-hydroxyphenyl, phenyl, 4-methylphenyl, 3-methylphenyl, —OCH₂CH₂OH or4-hydroxy-3-chlorophenyl.

Preferably, R³ is pyridyl or aryl, wherein the pyridyl and aryl are eachoptionally substituted with one or more substituents independentlyselected from the group consisting of:

halo,

—CN,

—CO₂H

OH,

CONR⁵R⁶

(C₁-C₆)alkyl (said (C₁-C₆)alkyl being optionally substituted with one ormore substituents independently selected from OH, NR⁵R⁶, aryl² andhalo),

—S(O)_(p)(C₁-C₆)alkyl (said —S(O)_(p)(C₁-C₆)alkyl being optionallysubstituted with one or more substituents independently selected fromOH, aryl² and halo),

(C₁-C₆)alkoxy (said (C₁-C₆)alkoxy being optionally substituted with oneor more substituents independently selected from OH, aryl² and halo),

—CO₂(C₁-C₆)alkyl (said —CO₂(C₁-C₆)alkyl being optionally substitutedwith one or more substituents independently selected from OH, aryl² andhalo),

(C₃-C₇)cycloalkyl (said (C₃-C₇)cycloalkyl being optionally substitutedwith one or more substituents independently selected from OH and halo),

pyridyl, and

aryl²,

or, alternatively, R³ is preferably (C₁-C₆)alkyl, optionally substitutedwith one or more substituents independently selected from OH, halo, and(C₁-C₆)alkoxy.

More preferably, R³ is aryl, optionally substituted with one or moresubstituents independently selected from the group consisting of:

halo,

OH,

(C₁-C₆)alkyl (said (C₁-C₆)alkyl being optionally substituted with one ormore substituents independently selected from OH and halo),

(C₁-C₆)alkoxy (said (C₁-C₆)alkoxy being optionally substituted with oneor more substituents independently selected from OH and halo),

or R³ is (C₁-C₆)alkyl.

Even more preferably, R³ is phenyl (optionally substituted with one ormore substituents independently selected from: Cl, F, OH, methyl, ethyl,isopropyl, CF₃, methoxy, ethoxy (said methoxy and ethoxy each beingoptionally substituted by OH),

or R³ is isopropyl.

In an alternative embodiment, R³ is preferably pyridyl or aryl, whereinthe pyridyl and aryl are each optionally substituted with one or moresubstituents independently selected from the group consisting of:

halo,

—CN,

—CO₂H

OH,

CONR⁵R⁶

(C₁-C₆)alkyl (said (C₁-C₆)alkyl being optionally substituted with one ormore substituents independently selected from OH, NR⁵R⁶, aryl² andhalo),

—S(O)_(p)(C₁-C₆)alkyl (said —S(O)_(p)(C₁-C₆)alkyl being optionallysubstituted with one or more substituents independently selected fromOH, aryl² and halo),

(C₁-C₆)alkoxy (said (C₁-C₆)alkoxy being optionally substituted with oneor more substituents independently selected from OH, aryl² and halo),

—CO₂(C₁-C₆)alkyl (said —CO₂(C₁-C₆)alkyl being optionally substitutedwith one or more substituents independently selected from OH, aryl² andhalo),

(C₃-C₇)cycloalkyl (said (C₃-C₇)cycloalkyl being optionally substitutedwith one or more substituents independently selected from OH and halo),

or, alternatively, R³ is preferably (C₁-C₆)alkyl, optionally substitutedwith one or more substituents independently selected from OH, halo, and(C₁-C₆)alkoxy.

More preferably, R³ is aryl, optionally substituted with one or moresubstituents independently selected from the group consisting of:

halo,

OH,

CN,

(C₁-C₈)alkyl (said (C₁-C₆)alkyl being optionally substituted with one ormore substituents independently selected from OH and halo),

(C₁-C₆)alkoxy (said (C₁-C₆)alkoxy being optionally substituted with oneor more substituents independently selected from OH and halo),

—S—(C₁-C₆)alkyl (said —S—(C₁-C₆)alkyl being optionally substituted withone or more substituents independently selected from OH and halo),

or R³ is (C₁-C₆)alkyl.

Even more preferably, R³ is phenyl (optionally substituted with one ormore substituents independently selected from: CN, Cl, F, OH, methyl,ethyl, isopropyl, CF₃, —S—(C₁-C₄)alkyl (said —S—(C₁-C₄)alkyl beingoptionally substituted by OH), methoxy, ethoxy (said ethoxy beingoptionally substituted by OH), or R³ is isopropyl.

Yet even more preferably, R³ is phenyl substituted with one or twosubstituents independently selected from Cl, F, CN, OH, —S-methyl, OCH₃,—SCH₂CH₂OH and —OCH₂CH₂OH.

In a particularly preferred embodiment of the invention, R³ issubstituted phenyl according to any one of the embodiments orpreferences herein, wherein the R³ phenyl is substituted with at leastone hydroxy substituent, or at least one hydroxyethoxy substituent, morepreferably at least one hydroxy substituent.

In another particularly preferred embodiment of the invention, R³ isphenyl substituted with:

2-hydroxy and 5-chloro,

2-hydroxy and 3-chloro,

3-hydroxy and 2-chloro,

5-hydroxy and 2-chloro,

3-cyano and 4-hydroxy,

2-hydroxy, or

2-OCH₂CH₂OH.

Preferably, when R³ is substituted phenyl and at least one substituentis —S—(C₁-C₆)alkyl, —S—(C₁-C₄)alkyl or —SCH₂CH₂OH, the —S—(C₁-C₆)alkyl,—S—(C₁-C₄)alkyl or —SCH₂CH₂OH is present at the ortho position (position2-) of the phenyl.

More preferably R³ is phenyl substituted with at least one substituentselected independently from —S-methyl and —SCH₂CH₂OH, wherein said—S-methyl or —SCH₂CH₂OH is present at the ortho position (position 2) ofthe phenyl.

Preferably, R⁵ and R⁶ are independently selected from H, methyl andethyl.

Preferably, “aryl” and “aryl²” are phenyl (optionally substituted withone or more substituents independently selected from halo, —CN, OH, andR⁸).

Preferably, R⁸ is (C₁-C₆)alkyl, (C₁-C₆)alkoxy or (C₃-C₇)cycloalkyl (each(C₁-C₆)alkyl, (C₁-C₆)alkoxy and (C₃-C₇)cycloalkyl being optionallysubstituted with one or more substituents independently selected from OHand halo).

More preferred R⁸ groups are CF₃, methyl, methoxy, ethyl, ethoxy,—OCH₂CH₂OH, —SCH₂CH₂OH, S-Me and cyclopropyl.

Preferably, p is 0.

Preferably, R⁹ is heteroaryl², heterocyclyl², aryl², aryl²oxy orheteroaryl²oxy;

More preferably, R⁹ is heteroaryl² or aryl².

Even more preferably, R⁹ is pyridyl or phenyl (said pyridyl or phenylbeing optionally substituted by one or more OH or halo).

Even more preferably, R⁹ is phenyl.

Another particularly preferred embodiment of the invention is thecompound of formula (I) according to any one of the embodiments orpreferences herein, wherein at least one of R² and R³ is substitutedphenyl, wherein said substituted phenyl is substituted with at least onehydroxy substituent or at least one hydroxyethoxy substituent, morepreferably at least one hydroxy substituent.

Preferably, “carbocyclyl” and “carbocyclyl²” are each independentlyselected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl (eachcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl optionallysubstituted with one or more OH).

Preferably, “heterocyclyl” and “heterocyclyl²” are each independentlyselected from pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, 1,4-dithianyl and piperazinyl (eachpyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, 1,4-dithianyl and piperazinyl optionally substituted withone or more OH).

Preferably, “heteroaryl”, and “heteroaryl²”, are each independentlyselected from pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, isoquinolinyl and pyrazinyl (each pyrazolyl, imidazolyl,tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, isoquinolinyl andpyrazinyl being optionally substituted with one or more OH).

More preferably, “heteroaryl” is pyridyl or isoquinolinyl, eachoptionally substituted with one or more OH.

According to another embodiment, a compound of formula (I), or apharmaceutically acceptable salt and/or solvate (including hydrate)thereof, wherein:

R¹ is CH₃, SCH₃, CH₂CH₃ or CH₂SCH₃;

R^(1a) is CH₃;

R² is pyridyl, isoquinolinyl or phenyl, said phenyl being optionallysubstituted with one or more substituents independently selected fromSCH₃, Cl, F, Br, ethyl, methyl, methoxy, OH, benzyloxy, CF₃, CO₂H,CO₂Et, CN, —OCO₂H, hydroxyethoxy, and —C(O)NHCH₃; andR³ is isopropyl or phenyl, said phenyl being optionally substituted withone or more substituents independently selected from Cl, OH, F,benzyloxy, methoxy, hydroxyethoxy, isopropyl, methyl, ethyl, SCH₃, CO₂H,hydroxyethylthio and CN; is preferred.

According to a further embodiment, a compound of formula (I), or apharmaceutically acceptable salt and/or solvate (including hydrate)thereof, wherein:

R¹ is CH₃, SCH₃, or CH₂SCH₃;

R^(1a) is CH₃;

R² is phenyl, said phenyl being optionally substituted with one or moresubstituents independently selected from SCH₃, Cl, OH, CN andhydroxyethoxy; and

R³ is isopropyl or phenyl, said phenyl being optionally substituted withone or more substituents independently selected from Cl, OH,hydroxyethoxy, SCH₃, hydroxyethylthio and CN; is more preferred.

In another embodiment there is provided a compound of formula (I)wherein each R¹, R^(1a), R² and R³ substituent is independently selectedfrom the substituents as defined in any of the preferred or alternativeembodiments herein, including any combination of said preferred oralternative embodiments.

A preferred group of compounds is that in which each substituent is asspecified in the Examples below.

Preferably, the compound of formula (I) is selected from a compound asspecified in the Examples below.

A preferred group of compounds is that in which each substituent is asspecified in the list¹ below.

Preferably, the compound of formula (I) is selected from the list¹:

list¹:

-   N-{3-tert-Butyl-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{3-tert-butyl-1-[3-(methylthio)phenyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(3,4-dichlorophenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   ethyl    4-(3-tert-butyl-5-{[({2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzoate,-   ethyl    3-(3-tert-butyl-5-{[({2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzoate,-   N-[3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea.-   N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(4-methoxy-3-methylphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{3-[1,1-Dimethyl-2-<methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N′-{3-[1-methyl-1-(methylthio)ethyl]1-phenyl-1H-pyrazol-5-yl}urea,-   N-{1-[2-(benzyloxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(4-chlorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,-   N-[2-({3-[2-benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}urea,-   N-[2-({3-[2-(benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-{1-(4-chlorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea,-   N-[2-({3-[2-(benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,-   N-[3-tert-Butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-Butyl-1-(4-hydroxy-3-methylphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(3-Hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}urea,-   N-{1-(4-chlorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea-   3-(3-tert-Butyl-5-{3-[2-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzyl]-ureido}-pyrazol-1-yl)-benzoic    acid,-   4-(3-tert-butyl-5-{[({2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzoic    acid,-   N-[3-tert-Butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-Butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-(3-tert-butyl-1-pyridin-3-yl-1H-pyrazol-5-yl)-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-pyridin-3-yl-1H-pyrazol-5-yl}urea,-   N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N′-[3-[1-methyl-1-(methylthio)ethyl]1-(4-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-(2-{[3-(2-Hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-[3-tert-Butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N-[3-[1-methyl-1-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-[3-tert-Butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{3-[1,1-dimethyl-2-(methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}urea,-   N-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-Butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-Butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-5-yl]thio}benzyl)urea,-   N-{1-(4-chlorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(3-ethylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(3-ethylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(3-ethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{3-tert-butyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{3-tert-butyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,-   N-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,-   N-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,-   N-{3-tert-butyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea-   N-{3-tert-butyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1-methyl-1-(methylthio)ethyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}urea,-   N-{1-(4-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(4-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(4-cyclopropylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(4-cyclopropylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(4-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(3-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(3-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(3-cyclopropylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(3-cyclopropylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(3-cyclopropylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(3,5-dimethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(3,5-dimethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea.-   N-[3-tert-butyl-1-(3,5-dimethylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(3,5-dimethylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(3,5-dimethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxy-4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(3-chloro-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-(isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(4-hydroxy-3-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(4-hydroxy-3-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(4-hydroxy-3-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(3-hydroxy-4-methylphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(3-hydroxy-4-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(3-hydroxy-4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(3-hydroxy-4-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(4-ethyl-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(4-ethyl-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(4-ethyl-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-{1-(4-ethyl-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea,-   N-[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea,-   N-[3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{1-(4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,-   N-{3-(2-hydroxy-1,1-dimethylethyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea-   N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(methylsulfinyl)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-[1,1-dimethyl-2-(methylsulfinyl)ethyl]-1-(3-fluorophenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea    and-   N-(1-(3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl)-N′-{2-[(3-phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,    and the salts, and/or solvates thereof.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate, adipate, cyclamate, tannate,pyroglutamate, xinafoate (1-hydroxynaphthalene-2-carboxylate) andtrifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

-   (i) by reacting the compound of formula (I) with the desired acid or    base;-   (ii) by removing an acid- or base-labile protecting group from a    suitable precursor of the compound of formula (I) or by ring-opening    a suitable cyclic precursor, for example, a lactone or lactam, using    the desired acid or base; or-   (iii) by converting one salt of the compound of formula (I) to    another by reaction with an appropriate acid or base or by means of    a suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August1975).

Hereinafter all references to compounds of formula (I) includereferences to salts, solvates, hydrates and complexes thereof and tosolvates and complexes of salts thereof.

The compounds of the invention include compounds of formula (I) ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of formula (I).

As indicated, so-called ‘pro-drugs’ of the compounds of formula (I) arealso within the scope of the invention. Thus certain derivatives ofcompounds of formula (I) which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into compounds of formula (I) having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found inPro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and Bioreversible Carriers in Drug Design,Pergamon Press, 1987 (ed. E. B. Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include

-   (i) where the compound of formula I contains a carboxylic acid    functionality (—COOH), an ester thereof, for example, a compound    wherein the hydrogen of the carboxylic acid functionality of the    compound of formula (I) is replaced by (C₁-C₈)alkyl;-   (ii) where the compound of formula (I) contains an alcohol    functionality (—OH), an ether thereof, for example, a compound    wherein the hydrogen of the alcohol functionality of the compound of    formula (I) is replaced by (C₁-C₆)alkanoyloxymethyl; and-   (iii) where the compound of formula (I) contains a primary or    secondary amino functionality (—NH₂ or —NHR where R≠H), an amide    thereof, for example, a compound wherein, as the case may be, one or    both hydrogens of the amino functionality of the compound of    formula (I) is/are replaced by (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of formula (I) may themselves act asprodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites ofcompounds of formula (I), that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include

-   (i) where the compound of formula (I) contains a (C₁-C₆)alkyl group,    the hydroxy(C₁-C₆)alkyl derivative thereof. For example where the    compound of formula (I) contains a methyl group, the hydroxymethyl    derivative thereof (—CH₃→—CH₂OH);-   (ii) where the compound of formula (I) contains an alkoxy group, an    hydroxy derivative thereof (—OR→—OH);-   (iii) where the compound of formula (I) contains a tertiary amino    group, a secondary amino derivative thereof (—NR⁵R⁶→—NHR⁵ or —NHR⁶);-   (iv) where the compound of formula (I) contains a secondary amino    group, a primary derivative thereof (—NHR⁵→—NH₂);-   (v) where the compound of formula (I) contains a phenyl moiety, a    phenol derivative thereof (-Ph→-PhOH);-   (vi) where the compound of formula (I) contains an amide group, a    carboxylic acid derivative thereof (—CONH₂→COOH); and-   (vii) where the compound of formula (I) contains a S—(C₁-C₆)alkyl    group, the S(O)(C₁-C₆)alkyl derivative thereof. For example, where    the compound of formula (I) contains a S-methyl group, the    S(O)methyl derivative thereof, and where the compound of formula (I)    contains an alkyl-S-alkyl group, the alkyl-S(O)-alkyl derivative    thereof.

In another aspect of the invention there is provided the activemetabolites of the compounds of formula (I), wherein “active” meanshaving an IC₅₀ (TNFα screen) of less than 1000 nM, and preferably anIC₅₀ (TNFα screen) of less than 100 nM. Preferably, there is provided acompound of formula (I) which contains a S(O)(C₁-C₆)alkyl group, or ahydroxy group.

Compounds of formula (I) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where structural isomers areinterconvertible via a low energy barrier, tautomeric isomerism(‘tautomerism’) can occur. This can take the form of proton tautomerismin compounds of formula (I) containing, for example, an imino, keto, oroxime group, or so-called valence tautomerism in compounds which containan aromatic moiety. It follows that a single compound may exhibit morethan one type of isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula (I), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or l-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine, Concentration ofthe eluate affords the enriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, Stereochemistry ofOrganic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York,1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, andsulphur, such as ³⁵S.

Certain isotopically-labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labelled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labelled reagent in placeof the non-labelled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Also within the scope of the invention are novel intermediates as hereindefined, all salts, solvates and complexes thereof and all solvates andcomplexes of salts thereof as defined herein for compounds of formula(I). The invention includes all polymorphs of the aforementioned speciesand crystal habits thereof.

When preparing compounds of formula (I) in accordance with theinvention, it is open to a person skilled in the art to routinely selectthe form of intermediate compound which provides the best combination offeatures for this purpose. Such features include the melting point,solubility, processability and yield of the intermediate form and theresulting ease with which the product may be purified on isolation.

The crystal structures of the compounds of example numbers 80, 26, 93,73, 63 and 60 were analyzed using powder X-ray diffraction (“PXRD”).

Illustrative PXRD patterns for these compounds are shown in FIGS. 1-6containing 15% silicon internal reference standard.

FIG. 1: Example 80

FIG. 2: Example 26

FIG. 3: Example 93

FIG. 4: Example 73

FIG. 5: Example 63

FIG. 6: Example 60

The X-ray diffraction data were collected at room temperature using aBruker AXS D4 powder X-ray diffractometer (Cu Kα radiation) fitted withan automatic sample changer, a theta-theta goniometer, automatic beamdivergence slits, a secondary monochromator and a scintillation counter.Samples were prepared for analysis by mixing the compound with a siliconpowder internal reference at 15% content by weight. The powders weremounted on a 12 mm diameter silicon wafer specimen holder. The samplewas rotated while being irradiated with Copper Kα1 X-rays(wavelength=1.5406 Ångstroms) with the X-ray tube operated at 40 kV/40mA. The analyses were performed with the goniometer running incontinuous mode set for a 5 second count per 0.02° step over a two thetarange of 2° to 55°. The peaks obtained were aligned against the siliconreference standard (ICDD reference number 001-0791).

As will be appreciated by the skilled crystallographer, the relativeintensities of the various peaks reported in the Tables and Figuresbelow may vary due to a number of factors such as orientation effects ofcrystals in the X-ray beam or the purity of the material being analyzedor the degree of crystallinity of the sample. The peak positions mayalso shift for variations in sample weight but the peak positions willremain substantially as defined in the Figures. The skilledcrystallographer also will appreciate that measurements using adifferent wavelength will result in different shifts according to theBragg equation—nλ=2d sin θ. Such further PXRD patterns generated by useof alternative wavelengths are considered to be alternativerepresentations of the PXRD patterns of the crystalline materials of thepresent invention and as such are within the scope of the presentinvention.

Tables 1-6 list the corresponding main diffraction peaks in terms of 2θvalues and intensities for the compounds excluding those peaks that canbe assigned to the silicon reference standard. All 2θ values are to+/−0.1 degree.

Table 1 lists the Example 80 peaks having a relative intensity greaterthan 33.0%.

Table 2 lists the Example 26 peaks having a relative intensity greaterthan 36.5%.

Table 3 lists the Example 93 peaks having a relative intensity greaterthan 15.5%.

Table 4 lists the Example 73 peaks having a relative intensity greaterthan 34.0%.

Table 5 lists the Example 63 peaks having a relative intensity greaterthan 35.7%.

Table 6 lists the Example 60 peaks having a relative intensity greaterthan 36.4%.

TABLE 1 Ex 80 Relative Intensity at least 33.0% Angle 2-Theta Relative(degrees) Intensity 15.4 39.2 18.0 34.7 18.8 68.6 19.5 81.1 21.1 100.021.5 33.9 24.1 50.3 24.7 40.7 25.7 42.6 26.4 42.0 27.8 33.0

TABLE 2 Ex 26 Relative Intensity at least 36.5% Angle 2-Theta Relative(degrees) Intensity 12.5 46.9 16.9 100.0 17.2 39.6 18.5 39.2 19.7 45.620.5 49.9 21.3 89.9 26.3 47.5 29.2 36.5

TABLE 3 Ex 93 Relative Intensity at least 15.5% Angle 2-Theta Relative(degrees) Intensity 15.5 79.1 17.2 19.4 18.3 100.0 18.8 16.5 19.5 19.120.6 15.6 21.1 18.0 23.4 15.8 25.0 15.6 26.0 15.5 27.1 35.1

TABLE 4 Ex 73: Relative Intensity at least 34.0% Angle 2-Theta Relative(degrees) Intensity 7.6 77.1 11.0 34.7 17.3 98.9 17.8 65.4 19.1 45.521.1 40.3 21.8 70.7 22.1 100.0 23.0 39.2 27.7 36.9 30.3 34.0

TABLE 5 Ex 63: Relative Intensity at least 35.7% Angle 2-Theta Relative(degrees) Intensity 13.6 70.6 18.1 49.6 19.6 45.2 21.0 50.0 22.3 62.722.5 35.7 23.2 100.0 24.2 53.1 25.8 44.7 26.5 39.4

TABLE 6 Ex 60: Relative Intensity at least 36.4% Angle 2-Theta Relative(degrees) Intensity 13.7 49.1 21.2 36.4 22.4 44.8 22.7 40.6 23.5 100.024.5 45.3 24.6 53.4 25.9 50.0 26.4 36.9

In a further aspect of the invention, there is provided a compound ofexample number 80, 26, 93, 73, 63 or 60, having the crystal structure asillustrated in the Figures and/or as defined in the Tables herein. Theinvention is by no means limited to said solid forms.

Compounds of formula (I) may be prepared, in a known manner, in avariety of ways. The following routes illustrate such ways of preparingthese compounds; the skilled man wilt appreciate that other routes maybe equally as practicable. In the following schemes, unless otherwisestated, the substituents are as defined above with reference to thecompounds of formula (I) above, and

“PdCl₂(dppf).CH₂Cl₂” is 1,1-bis(diphenylphosphino)ferrocene palladium(II) chloride 1:1 dichloromethane complex

“DBU” is 1,8-diazabicyclo[5.4.0]undec-7-ene

“BOC” means tert-butoxycarbonyl;

“CBz” means benzyloxycarbonyl

“Et” means ethyl

“Me” means methyl

“Pd” means palladium, and

“eq” means mole equivalent(s)

“iPr” means isopropyl.

Compounds of general formula (II) are either commercially available orcan be prepared as shown in scheme 2.

Compounds of general formula (III) are either commercially available(e.g. when R^(1a)=Me and R¹=Me) or can be prepared as shown in scheme 3.

Compounds of general formula (IV) can be prepared from compounds offormula (II) and (III) by process step i—cyclocondensation of compound(II) and compound (III) optionally in the presence of a suitable acidcatalyst such as hydrochloric acid, optionally in the presence of asuitable base such as Hünig's base, triethylamine or pyridine, in asuitable solvent such as methanol or ethanol, at elevated temperaturefor 3-24 hours. Typical conditions comprise of 1.0-1.3 equivalents ofcompound (II) and 1.0-1.1 equivalents of compound (III) in the presenceof hydrochloric acid, in ethanol, heated under reflux for 3-24 hours.

Additionally, compounds of general formula (IV) can be obtained bydirect condensation of compounds of formula (VII) with compounds offormula (III), in EtOH/HCl.

Compounds of general formula (V) can be prepared as shown in scheme 4.

Compounds of formula (I) can be prepared from compounds (IV) and (V) byprocess step ii—urea formation is achieved by reaction of compound (IV)in the presence of a suitable carbonyl source such asN,N′-carbonyldiimidazole, phenylchloroformate orbis(trichloromethyl)carbonate and a suitable base such as Hünig's baseor pyridine, in a suitable solvent such as dichloromethane or 1,4dioxane, under ambient conditions for 48 hours, followed by addition ofcompound (V). Typical conditions comprise of either:

-   -   a) 1.0 equivalent of compound (IV) and 5.0-6.0 equivalents of        N,N′-carbonyldiimidazole in dichloromethane, under ambient        conditions for 24 hours,    -   b) 0.25-0.80 equivalents of compound (V), 0.25-1.25 equivalents        of Hünig's base in dichloromethane or 1,4 dioxane, under ambient        conditions for 24 hours, or    -   c) 1 equivalent of compound (IV) and 1 equivalent of        phenylchloroformate in THF/pyridine, followed by 0.8-1        equivalent of compound (V) in DMSO.

When R² is aryl or heteroaryl, compounds of general formula (II) may beprepared as shown in scheme 2.

Where R²—Br is not available, the compound of formula (II) could beprepared from the corresponding aniline derivative by diazotisationfollowed by reduction, using conditions well-known in the chemicalliterature.

PG is a suitable protecting group such as BOC or CBz and preferably BOC.

Where R² is, or includes, a phenol, the skilled person will appreciatethat it may be necessary to use a protecting group, typically benzyloxyor methyloxy.

Compounds of general formula (VI) are commercially available.

Compounds of general formula (II) can be prepared from compounds ofgeneral formula (VI), via compound (VII), by process steps (iii) and(iv).

Step (iii)—is achieved by formation of a suitable organometallic reagente.g. arylMgBr, heteroarylMgBr, arylLi, or heteroarylLi, optionallyprepared in situ under standard Grignard conditions or by reaction witha suitable alkyl lithium, e.g. ^(n)BuLi, in a suitable solvent such astetrahydrofuran or diethyl ether, at a temperature between −100° C. to25° C., for 1-18 hours. The intermediate compound (VII) is formed bysubsequent nucleophilic attack of a suitably protected diazocarboxylatecompound, preferably di-tert-butyldiazocarboxylate, byarylMgBr/heteroarylMgBr/arylLi/heteroarylLi, in a suitable solvent suchas tetrahydrofuran or diethyl ether, at −78° C. for 0.5-1.0 hours.

Step (iv)—Deprotection of compound (VII) using standard methodology asdescribed in “Protecting Groups in Organic Synthesis” by T. W. Greeneand P. Wutz. When PG=BOC, typical conditions involve saturation ofintermediate (VII) with a suitable acid such as hydrochloric acid ortrifluoroacetic acid, in a suitable solvent such as isopropyl alcohol,1,4-dioxane or diethyl ether, under ambient conditions for 2-18 hours.

More preferably, compounds of general formula (II) can be prepared fromcompounds of formula (VI) by a combination of steps iii and iv in aone-pot synthesis. Typical conditions comprise of

-   -   a) 1.0 equivalent of compound (VI), 1.1 equivalents of magnesium        turnings and a single crystal of iodine in tetrahydrofuran, at        room temperature for 18 hours, followed by addition of        di-tert-butyldiazocarboxylate at −78° C., for 30 minutes.    -   b) Saturation with hydrochloride gas in isopropyl alcohol, under        ambient conditions for 0.5-1.0 hours.

When R² represents heterocyclyl or carbocyclyl, compounds of generalformula (II) may be prepared according to scheme 2.1.

Step (xvii)—Compounds of formula (XXVII) may be prepared from compoundsof formula (VI) by reaction with a suitable protected hydrazine (e.g.BOC—NHNH₂) in the presence of a suitable alkali metal base (e.g. K₂CO₃or Na₂CO₃) in a suitable solvent such as acetonitrile orN,N-dimethylformamide at between ambient temperature and 60° C. for upto48 hours.

Compounds of formula (II) may be prepared from compounds of formula(XXVII) using the methods described previously for step iv.

Compounds of general formula (III) may be prepared according to schemes3.1 and 3.2.

When R¹=—(CH₂)_(n)SR^(b), compounds of formula (III) can be prepared asshown in scheme 3.1. R^(b) represents methyl or ethyl.

n represents 0 or 1.

LG is a suitable leaving group, e.g. OR′ or Cl and is preferably OR′.

R′ represents C₁-C₄ alkyl, and preferably C₁-C₂ alkyl.

When R′=Et or Me, compounds of formula (VIII) are commerciallyavailable.

When n=1, compounds of formula (IXA) can be prepared from compounds offormula (VIII) by process step v—nucleophilic substitution. The reactionproceeds via the formation of an intermediate containing a suitableleaving group LG′, such as mesylate or tosylate by reaction of compound(VIII) with mesyl chloride/anhydride or tosyl chloride, in the presenceof a suitable base such as Hünig's base, triethylamine or pyridine, in asuitable solvent such as dichloromethane or diethyl ether, at lowtemperature for 1-2 hours. Concentration in vacuo is followed by theaddition 1,4-dioxane or toluene and methanethiol sodium salt, heatingunder reflux for 24 hours. Typical conditions comprise of

-   -   a) 1.0 eq of compound (VIII), 1.0-1.2 eq of Hünig's base, and        1.1 eq of methane sulfonyl chloride in dichloromethane, at 0° C.        for 1-2 hours.    -   b) 1.1 eq methanethiol sodium salt in 1,4-dioxane, heating under        reflux for 24 hours.

When n=0, compounds of formula (IXA) are commercially available

Compound (III) can be prepared from compounds of formula (IXA) byprocess step vi—reaction with acetonitrile (X). Treatment of (X) with asuitable base such as sodium hydride or lithium diisopropylamide,followed by quench of the intermediate anion with compound (IXA), in asuitable solvent such as tetrahydrofuran, at elevated temperature for 3hours provides compounds of formula (III). Typical conditions compriseof 1.3 eq acetonitrile, 1.3 eq sodium hydride (60% dispersion in mineraloil) and 1.0 equivalent of compound (IXA) in tetrahydrofuran, heatedunder reflux for 3 hours.

When R^(1a) represents H, CH₃ or CH₂CH₃, compounds of formula (III) maybe prepared as shown in scheme 3.2.

LG is a suitable leaving group, e.g. OR′ or Cl and is preferably OR′.

R′ represents C₁-C₄ alkyl, and preferably C₁-C₂ alkyl.

Compounds of formula (III) may be prepared from compounds of formula(IXB) by process step vi, as described previously.

Compounds of formula (IXB) are either available commercially, or may beprepared by analogy with the methods of Julia et. al. Bull. Soc. Chim.Fr. 1996; 133(1); 15-24, or Chuit et. al. Tetrahedron 1980; 36(16),2305-10.

Compounds of formula (V) may be prepared as shown in scheme 4

When Y=halogen and is preferably bromo, compounds of general formula(XI) are commercially available.

Compounds of formula (XII) can be prepared from compounds of formula(XI) by process step vii—reaction with hydrazine monohydrate, optionallyin a suitable solvent such as methanol or ethanol, at elevatedtemperature for 18-72 hours. Typical conditions comprise 1.0 eq ofcompound (XI) and an excess of hydrazine monohydrate heated to 70° C.for 72 hours.

Compounds of formula (XIV) can be prepared from compounds of formula(XII) by process step viii—reaction with a suitable alkoyl chlorideR³C(O)Cl (XIII), in the presence of a suitable base such as Hünig'sbase, triethylamine or pyridine in a suitable solvent such asdichloromethane or diethyl ether, at low temperature for 1-2 hours.Typical conditions comprise of 1.0 eq of compound (XII), 1.0 eq ofR³C(O)Cl (XIII) and 5.0 eq Hünig's base in dichloromethane, at atemperature between 0-5° C. for 1-2 hours.

Compounds of formula (XV) can be prepared from compounds of formula(XIV) by process step ix—cyclisation. This is achieved by use of asuitable dehydrating agent such as phosphorus oxychloride or phosphorus(V) oxide in sulfuric acid, at elevated temperature for 18-24 hours.Typical conditions comprise of 1.0 equivalent of compound (XIV) in anexcess of phosphorus oxychloride, at 75°G for 18-24 hours.

Alternatively, compounds of formula (XV) can be prepared directly fromcompounds of formula (XII) by process step ix. This cyclisation isachieved by reaction with an excess of compound (XIII) and heated, forexample at 95° C., for 18-24 hours.

Compounds of formula (XVII) can be prepared from compounds of formula(XV) by process step x—Pd catalysed cross coupling reaction with2-mercaptobenzyl alcohol (XVI), in the presence of a suitable catalystsuch as PdCl₂(dppf).CH₂Cl₂, in the presence of a suitable base such ascesium carbonate or potassium carbonate, in a suitable solvent such asN,N-dimethylformamide or 1,4-dioxane, at elevated temperature for 2-48hours. Typical conditions comprise of 1.0 eq compound (XV), 1.2-1.4 eqcesium carbonate, 1.3 eq 2-mercaptobenzyl alcohol (XVI) and 0.1 eqPdCl₂(dppf).CH₂Cl₂ in N,N-dimethylformamide, at elevated temperature for18 hours.

Compounds of formula (XVIII) can be prepared from compounds of formula(XVII) by process step xi—azide formation. This proceeds by reaction ofcompound (XVII) with a suitable base such as DBU or sodium hydride,followed by reaction with a suitable azide such as diphenylphosphorylazide in a suitable solvent such as toluene or tetrahydrofuran, at atemperature between 0-25° C. for 18-24 hours. Typical conditionscomprise of 1.0 eq of compound (XVII), 1.2 eq of DBU and 1.2 eqdiphenylphosphoryl azide in toluene at 0-25° C. for 24 hours.

Compounds of formula (V) can be prepared from compounds of formula(XVIII) by process step xii—reduction of compound (XVIII) with asuitable reducing agent such as triphenyl phosphine/water, tin chlorideor catalytic hydrogenation, in a suitable solvent such astetrahydrofuran or ethanol, between ambient and elevated temperature.Typical conditions comprise of 1.0 eq compound (XVIII), 1.2 eqtriphenylphosphine and 1.2 eq of water in tetrahydrofuran, at roomtemperature for 40 hours and at 50° C. for 5 hours.

Alternatively, compounds of formula (V) can also be prepared as shown inscheme 5

Compounds of formula (XII) can be prepared as described in scheme 4.

Compounds of formula (XIX) are either commercially available or can beprepared as described in scheme 6

Compounds of formula (XX) can be prepared from compounds of formula(XII) and (XIX) by process step xiii—condensation of hydrazine (XII) andaldehyde (XIX) in a suitable solvent such as methanol, ethanol ortoluene, at elevated temperature for 0.5-1 hour. Typical conditionscomprise of 1 eq of compound (XII) and 1 eq of compound (XIX) inethanol, heated at reflux for 0.5-1.0 hour.

Compounds of formula (XV) can be prepared from compounds of formula (XX)by process step xiv—cyclisation of compound (XX) in the presence of asuitable oxidising agent such as (diacetoxyiodo)benzene, cerium (IV)ammonium nitrate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in asuitable solvent such as ethyl acetate, dichloromethane or acetonitrile,under ambient conditions for 18-24 hours. Typical conditions comprise of1.0 eq of compound (XX) and 1.2 eq of (diacetoxyiodo)benzene indichloromethane, at room temperature for 24 hours.

Alternatively, compounds of formula (XV) can be prepared from compound(XII) by process steps xiii and xiv in a one-pot synthesis. Typicalconditions comprise of 1 eq of compound (XII) and 1 eq of compound (XIX)in ethanol, heated at reflux for 0.5-1.0 hour, followed by addition of1.2 eq of (diacetoxyiodo)benzene and dichloromethane, at roomtemperature for 24 hours.

Compounds of formula (XVII) can be prepared from compounds of formula(XV) and (XVI) by process step x as described in scheme 4.

Compounds of formula (XVIII) can be prepared from compounds of formula(XVII) by process step xi as described in scheme 4.

Compounds of formula (V) can be prepared from compounds of formula(XVIII) by process step xii as described in scheme 4.

Alternatively, compounds of formula (V) can be also be prepared fromcompounds of formula (XVII) by process step xviii—The reaction proceedsvia the formation of an intermediate containing a suitable leaving groupsuch as mesylate or tosylate by reaction of compound (VIII) with mesylchloride/anhydride or tosyl chloride, in the presence of a suitable basesuch as Hünig's base, triethylamine or pyridine, in a suitable solventsuch as dichloromethane or diethyl ether, at low to ambient temperaturefor 1-4 hours. The resulting intermediate is then treated with asuitable source of ammonia, typically 7M ammonia in methanol, underambient conditions for 18-72 hours. Typical conditions comprise of 1.0eq of compound (XVII), 3.0-4.0 eq of Hünig's base, and 2.0-3.0 eq ofmethane sulfonyl anhydride in dichloromethane, at 25° C. for 1-4 hours.Excess 7M ammonia in methanol is added and reaction is stirred atambient temperature for 18-72 hours.

Alternatively compounds of formula (V) can be prepared from compounds offormula (XV) and compound of formula (XXVII) where PG is a protectinggroup, such as BOC. Typical conditions comprise of 1 eq of compound(XV), 1.2 eq of compound (XXVII), 1.2 eq of anhydrous cesium carbonate,3 eq of cesium fluoride, 0.1 eq of PdCl₂(dppf).CH₂Cl₂ indimethylformamide as solvent at 80-100° C. for 2-48 h.

The product of this reaction is then subject to acid-mediated removal ofthe BOC group to afford compounds of formula (V).

Compounds of formula (XXVII) can be prepared from compounds of formula(XXVIII) by process step xix (Scheme 5.1). The reaction proceeds by apalladium-catalysed insertion of the sulfide into an aromatic-brominebond.

Typical conditions comprise of 1 eq of compound (XXVIII), 1 eq ofpotassium tri(isopropyl)silylsulfide (formed from 1 eq of potassiumtert-butoxide and 1 eq of triisopropylsilanethiol in toluene), 1 eq ofPdCl₂(dppf).CH₂Cl₂ in toluene as solvent at 100° C. for 0.5 to 2 h.

Where R³ is, or includes, a phenol, the skilled person will appreciatethat it may be necessary to use a protecting group, typically benzyloxyor methyloxy.

Compounds of formula (XXIV) are commercially available

Compounds of formula (XXV) can be prepared from compounds of formula(XXIV) by process step xv—reduction with a suitable reducing agent suchas lithium aluminium hydride, diisobutylaluminium hydride or sodiumborohydride in a suitable solvent such as tetrahydrofuran or methanol,at elevated temperature for 6-18 hours. Typical conditions comprise of1.0 eq of compound (XXIV) and 1.0-1.2 eq of lithium aluminium hydride intetrahydrofuran, at reflux for 6 hours.

Compounds of formula (XIX) can be prepared from compounds of formula(XXV) by process step xvi—oxidation with a suitable oxidising agent suchas manganese dioxide, potassium permanganate or oxalylchloride/dimethylsulfoxide, in a suitable solvent such as acetone,dichloromethane or dimethylsulfoxide, at from −80 to +80° C. for 3-18hours. Typical conditions comprise of 1.0 eq of compound (XXV) and 0.5eq of manganese dioxide in acetone, heated under reflux for 3 hours.

Alternatively, compounds of formula (XIX) can be prepared fromcommercial compounds of formula (XXVI) by process step xvii—reduction ofnitrile by diisobutylaluminium hydride in a suitable solvent such astetrahydrofuran, at low temperature. Typical conditions comprise of

-   -   a) 1.0 equivalent of compound (XXVI) and 1.0-2.0 equivalents of        diisobutylaluminium hydride in tetrahydrofuran, at −78° C. for 1        hour,    -   b) excess hydrochloric acid and water at 0° C.

It will be appreciated by those skilled in the art that it may benecessary or desirable at any stage in the synthesis of compounds offormula (I) to protect one or more sensitive groups in the molecule soas to prevent undesirable side reactions. In particular, it may benecessary or desirable to protect phenol groups. The protecting groupsused in the preparation of compounds of formula (I) may be used in aconventional manner. See, for example, those described in ‘ProtectiveGroups in Organic Synthesis’ by Theodora W Green and Peter G M Wuts,third edition, (John Wiley and Sons, 1999), in particular chapter 2,pages 17-245 (“Protection for the Hydroxyl Group”). Alternatively, theprotected phenols are available commercially. Removal of such groups canbe achieved using conventional methods.

It will be still further appreciated that compounds of formula (I) mayalso be converted to alternative compounds of formula (I) using standardchemical reactions and transformations. For example, when X (wherein Xis a group as shown in the Examples and Preparations herein) is anester, compounds of formula (I) can undergo saponification to give thecarboxylic acid derivative. When X=aryloxy, compound (I) can undergode-alkylation using boron tribromide or HBr/acetic acid to give thecorresponding phenol. Furthermore when X═OH, hydroxyalkoxy derivativescan be prepared by reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyranfollowed by de-protection of the primary alcohol, using boron tribromideor para-toluenesulfonic acid.

In another embodiment of the invention, there is provided a process formaking a compound of formula (I), wherein the substituents are asdefined in claim 1 and the description related to the processes, whichcomprises the steps:

i: cyclocondensation of a compound of formula (II) and a compound offormula (III) to make a compound of formula (IV):

and/orii: urea formation, by reaction of a compound of formula (IV) with acompound of formula (V), in the presence of a suitable carbonyl source.

In another embodiment of the invention, there is provided a process formaking a compound of formula (V), wherein the substituents are asdefined in the description related to the processes, which comprises thesteps:

xi: azide formation, by reaction of a compound of formula (XVII), with asuitable base, followed by reaction with a suitable azide, to form acompound of formula (XVIII)

and/orxii: reduction of a compound of formula (XVIII) to form a compound offormula (V)

In another embodiment of the invention, there is provided a novelprocess as described herein.

In another embodiment of the invention, there is provided anintermediate compound of formula (IV), (V), (XVII) or (XVIII), whereinthe substituents are as described herein.

In another embodiment of the invention, there is provided a novelintermediate compound of a formula as described herein.

Another aspect of the invention is a compound of formula (I) asdescribed herein, or a salt and/or solvate thereof, for use in medicine.

Another aspect of the invention is a compound of formula (I) asdescribed herein, or a salt and/or solvate thereof, for use in treatinga disease, disorder, or condition selected from the group consisting of:

-   -   1. asthma of whatever type, etiology, or pathogenesis, in        particular asthma that is a member selected from the group        consisting of atopic asthma, non-atopic asthma, allergic asthma,        atopic bronchial IgE-mediated asthma, bronchial asthma,        essential asthma, true asthma, intrinsic asthma caused by        pathophysiologic disturbances, extrinsic asthma caused by        environmental factors, essential asthma of unknown or inapparent        cause, non-atopic asthma, bronchitic asthma, emphysematous        asthma, exercise-induced asthma, allergen induced asthma, cold        air induced asthma, occupational asthma, infective asthma caused        by bacterial, fungal, protozoal, or viral infection,        non-allergic asthma, incipient asthma, wheezy infant syndrome        and branchiolytis,    -   2. chronic or acute bronchoconstriction, chronic bronchitis,        small airways obstruction, and emphysema,    -   3. obstructive or inflammatory airways diseases of whatever        type, etiology, or pathogenesis, in particular an obstructive or        inflammatory airways disease that is a member selected from the        group consisting of chronic eosinophilic pneumonia, chronic        obstructive pulmonary disease (COPD), COPD that includes chronic        bronchitis, pulmonary emphysema or dyspnea associated or not        associated with COPD, COPD that is characterized by        irreversible, progressive airways obstruction, adult respiratory        distress syndrome (ARDS), exacerbation of airways        hyper-reactivity consequent to other drug therapy and airways        disease that is associated with pulmonary hypertension,    -   4. bronchitis of whatever type, etiology, or pathogenesis, in        particular bronchitis that is a member selected from the group        consisting of acute bronchitis, acute laryngotracheal        bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus        bronchitis, dry bronchitis, infectious asthmatic bronchitis,        productive bronchitis, staphylococcus or streptococcal        bronchitis and vesicular bronchitis,    -   5. acute lung injury,    -   6. bronchiectasis of whatever type, etiology, or pathogenesis,        in particular bronchiectasis that is a member selected from the        group consisting of cylindric bronchiectasis, sacculated        bronchiectasis, fusiform bronchiectasis, capillary        bronchiectasis, cystic bronchiectasis, dry bronchiectasis and        follicular bronchiectasis.

A further aspect of the invention is the use of a compound of formula(I) as described herein, or a salt and/or solvate thereof, in themanufacture of a medicament for the treatment of a disease, disorder, orcondition disclosed in paragraphs 1-6 above.

A further aspect of the invention is the use of a compound of formula(I) as described herein, or a salt and/or solvate thereof, in themanufacture of a medicament for the treatment of a p38-mediated disease,disorder or condition or a TNF-mediated disease, disorder, or condition.

Another aspect of the invention is a compound of formula (I) asdescribed herein, or a salt and/or solvate thereof, for use in treatinga p38-mediated disease, disorder or condition or a TNF-mediated disease,disorder, or condition.

The present invention provides a method of treating a mammal, includinga human being, with an effective amount of a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof.

More precisely, the present invention provides a method of treating ap38-mediated disease, disorder or condition or a TNF-mediated disease,disorder, or condition in a mammal, including a human being, inparticular a disease disorder, or condition listed above, comprisingadministering said mammal with an effective amount of a compound offormula (I), or a salt and/or solvate thereof.

Preferably, the present invention provides a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, for use intreating obstructive or inflammatory airways diseases of whatever type,etiology, or pathogenesis, in particular an obstructive or inflammatoryairways disease that is a member selected from the group consisting ofchronic eosinophilic pneumonia, chronic obstructive pulmonary disease(COPD), COPD that includes chronic bronchitis, pulmonary emphysema ordyspnea associated or not associated with COPD, COPD that ischaracterized by irreversible, progressive airways obstruction, adultrespiratory distress syndrome (ARDS), exacerbation of airwayshyper-reactivity consequent to other drug therapy and airways diseasethat is associated with pulmonary hypertension, or asthma of whatevertype, etiology, or pathogenesis, in particular asthma that is a memberselected from the group consisting of atopic asthma, non-atopic asthma,allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma,essential asthma, true asthma, intrinsic asthma caused bypathophysiologic disturbances, extrinsic asthma caused by environmentalfactors, essential asthma of unknown or inapparent cause, non-atopicasthma, bronchitic asthma, emphysematous asthma, exercise-inducedasthma, allergen induced asthma, cold air induced asthma, occupationalasthma, infective asthma caused by bacterial, fungal, protozoal, orviral infection, non-allergic asthma, incipient asthma, wheezy infantsyndrome and bronchiolytis.

More preferably, the present invention provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for usein treating chronic obstructive pulmonary disease (COPD).

Preferably, the present invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for treating obstructive orinflammatory airways diseases of whatever type, etiology, orpathogenesis, in particular an obstructive or inflammatory airwaysdisease that is a member selected from the group consisting of chroniceosinophilic pneumonia, chronic obstructive pulmonary disease (COPD),COPD that includes chronic bronchitis, pulmonary emphysema or dyspneaassociated or not associated with COPD, COPD that is characterized byirreversible, progressive airways obstruction, adult respiratorydistress syndrome (ARDS), exacerbation of airways hyper-reactivityconsequent to other drug therapy and airways disease that is associatedwith pulmonary hypertension, or asthma of whatever type, etiology, orpathogenesis, in particular asthma that is a member selected from thegroup consisting of atopic asthma, non-atopic asthma, allergic asthma,atopic bronchial IgE-mediated asthma, bronchial asthma, essentialasthma, true asthma, intrinsic asthma caused by pathophysiologicdisturbances, extrinsic asthma caused by environmental factors,essential asthma of unknown or inapparent cause, non-atopic asthma,bronchitic asthma, emphysematous asthma, exercise-induced asthma,allergen induced asthma, cold air induced asthma, occupational asthma,infective asthma caused by bacterial, fungal, protozoal, or viralinfection, non-allergic asthma, incipient asthma, wheezy infant syndromeand bronchiolytis.

More preferably, the present invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for treating chronic obstructivepulmonary disease (COPD).

As used herein, the term “TNF-mediated disease”, or “TNF-mediateddisorder” or “TNF-mediated condition” refers to any disease, disorder,or condition (particularly any pathological conditions), respectively,in which TNF plays a role, either by control of TNF itself, or by TNFcausing another monokine to be released, such as, for example, IL-1,IL-6, and/or IL-8. A disease state in which, for instance, IL-1 is amajor component and whose production or action is exacerbated orsecreted in response to TNF, would therefore be considered a disordermediated by TNF.

As used herein, the term “p38-mediated disease”, or “p38-mediateddisorder” or “p38-mediated condition” refers to any disease, disorder,or condition (particularly any pathological conditions), respectively,in which p38 plays a role, either by control of p38 itself, or by p38causing another monokine to be released, such as, for example, IL-1,IL-6, and/or IL-8. A disease state in which, for instance, IL-1 is amajor component and whose production or action is exacerbated orsecreted in response to p38, would therefore be considered a disordermediated by p38.

The compounds of the invention can be used in the treatment of aTNF-mediated disease, disorder, or condition, or a p38-mediated disease,disorder or condition, in particular the allergic and non-allergicairways diseases disclosed above, but also in the treatment of p38- orTNF-mediated conditions such as:

(a) inflammation;

(b) arthritis, such as rheumatoid arthritis, spondyloarthropathies,gouty arthritis, osteoarthritis, systemic lupus erythematosus arthritis,juvenile arthritis, osteoarthritis, and gouty arthritis;

(c) neuroinflammation;

(d) pain (i.e., use of the compounds as analgesics), such as neuropathicpain;

(e) fever (i.e., use of the compounds as antipyretics);

(f) pulmonary sarcoisosis, and silicosis;

(g) cardiovascular diseases, such as atherosclerosis, myocardialinfarction (such as post-myocardial infarction indications), thrombosis,congestive heart failure, cardiac reperfusion injury, and complicationsassociated with hypertension and/or heart failure such as vascular organdamage;(h) cardiomyopathy;(i) stroke, such as ischemic and hemorrhagic stroke;(j) ischemia, such as brain ischemia and ischemia resulting fromcardiac/coronary bypass;(k) reperfusion injury;(l) renal reperfusion injury;(m) brain edema;(n) neurotrauma and brain trauma, such as closed head injury;(O) neurodegenerative disorders;(p) central nervous system disorders (these include, for example,disorders having an inflammatory or apoptotic component), such asAlzheimer's disease, Parkinson's disease, Huntington's Disease,amyotrophic lateral sclerosis, spinal cord injury, and peripheralneuropathy;(q) liver disease and nephritis;(r) gastrointestinal conditions, such as inflammatory bowel disease,Crohn's disease, gastritis, irritable bowel syndrome, and ulcerativecolitis;(s) ulcerative diseases, such as gastric ulcer;(t) ophthalmic diseases, such as retinitis, retinopathies (such asdiabetic retinopathy), uveitis, ocular photophobia, nonglaucomatousoptic nerve atrophy, and age-related macular degeneration (ARMD) (suchas ARMD-atrophic form);(u) opthalmological conditions, such as corneal graft rejection, ocularneovascularization, retinal neovascularization (such asneovascularization following injury or infection), and retrolentalfibroplasia;(v) glaucoma, such as primary open angle glaucoma (POAG), juvenile onsetprimary open-angle glaucoma, angle-closure glaucoma, pseudoexfoliativeglaucoma, anterior ischemic optic neuropathy (AION), ocularhypertension, Reiger's syndrome, normal tension glaucoma, neovascularglaucoma, ocular inflammation, and corticosteroid-induced glaucoma;(w) acute injury to the eye tissue and ocular traumas, such aspost-traumatic glaucoma, traumatic optic neuropathy, and central retinalartery occlusion (CRAO);(x) diabetes;(y) diabetic nephropathy;(z) skin-related conditions, such as psoriasis, eczema, burns,dermatitis, keloid formation, scar tissue formation, and angiogenicdisorders;(aa) viral and bacterial infections, such as sepsis, septic shock, gramnegative sepsis, malaria, meningitis, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, rhinovirus infections, and herpes virus;(bb) myalgias due to infection;(cc) influenza;(dd) endotoxic shock;(ee) toxic shock syndrome;(ff) autoimmune disease, such as graft vs. host reaction and allograftrejections;(gg) bone resorption diseases, such as osteoporosis;(hh) multiple sclerosis;(ii) disorders of the female reproductive system, such as endometriosis;(jj) pathological, but non-malignant, conditions, such as hemaginomas(such as infantile hemaginomas), angiofibroma of the nasopharynx, andavascular necrosis of bone;(kk) benign and malignant tumors/neoplasia including cancer, such ascolorectal cancer, brain cancer, bone cancer, epithelial cell-derivedneoplasia (epithelial carcinoma) such as basal cell carcinoma,adenocarcinoma, gastrointestinal cancer such as lip cancer, mouthcancer, esophageal cancer, small bowel cancer and stomach cancer, coloncancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer,cervical cancer, lung cancer, breast cancer, skin cancer such as squamuscell and basal cell cancers, prostate cancer, renal cell carcinoma, andother known cancers that affect epithelial cells throughout the body;(ll) leukemia;(mm) lymphoma, such as B cell lymphoma;(nn) systemic lupus erthrematosis (SLE);(oo) angiogenesis including neoplasia;(pp) metastasis;(qq) a fibrotic disease;(rr) hemorrhage;(ss) coagulation;(tt) acute phase responses like those seen with infections and sepsisand during shock (e.g., (uu) septic shock, hemodynamic shock, etc.);(vv) anorexia;(ww) mycobacterial infection;(xx) pseudorabies,(yy) rhinotracheitis,(zz) HIV,(aaa) influenza virus,(bbb) herpes virus, including herpes simplex virus type-1 (HSV-1),herpes simplex virus type-2 (HSV) 2).(ccc) cytomegalovirus (CMV),(ddd) varicella-zoster virus (VZV),(eee) Epstein-Barr virus,(fff) human herpesvirus-6 (HHV-6),(ggg) human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8).

In another embodiment of the invention, there is a compound of formula(I), or a salt and/or solvate thereof, for use in treating a disease,disorder, or condition, selected from the list (a) to (ggg) above.

A further embodiment of the invention is the use of a compound offormula (I), or a salt and/or solvate thereof, in the manufacture of amedicament for treating a disease, disorder, or condition selected fromthe list (a) to (ggg) above.

A yet further embodiment of the invention is a method of treating adisease, disorder, or condition selected from the list (a) to (ggg)above, in a mammal, including a human being, comprising administeringsaid mammal with an effective amount of a compound of formula (I), or asalt and/or solvate thereof.

The compounds of the invention can also be used in the treatment of ap38- or TNF-mediated disease such as smoke-induced airway inflammation,inflammation enhanced cough, for the control of myogenesis, for treatingmucin overproduction, and/or for treating mucus hypersecretion.

As TNF-β has close structural homology with TNF-α (also known ascachectin), and because each induces similar biologic responses andbinds to the same cellular receptor, the synthesis of both TNF-α andTNF-β tend to be inhibited by the compounds of this invention and thusare herein referred to collectively as “TNF” unless specificallydelineated otherwise.

A compound of formula (I), or a pharmaceutically acceptable salt and/orsolvate thereof, as mentioned above, can be administered according tothe invention to animals, preferably to mammals, and in particular tohumans, as pharmaceuticals.

The compound can be administered per se, in a mixture with one or moreother compounds of the invention, or in the form of pharmaceuticalpreparation, which, as active constituent contains an efficacious doseof at least one compound of the invention, in addition to customarypharmaceutically innocuous excipients and/or additives.

The compounds of the invention intended for pharmaceutical use may beadministered as crystalline or, amorphous products. They may beobtained, for example, as solid plugs, powders, or films by methods suchas precipitation, crystallization, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof). Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients. The term ‘excipient’ is usedherein to describe any ingredient other than the compound(s) of theinvention. The choice of excipient will to a large extent depend onfactors such as the particular mode of administration, the effect of theexcipient on solubility and stability, and the nature of the dosageform.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in Remington'sPharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled), chews, multi- and nanoparticulates,gels, solid solution, liposome, films, ovules, sprays and liquidformulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents and/or suspending agents. Liquidformulations may also be prepared by the reconstitution of a solid, forexample, from a sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1weight % to 80 weight % of the dosage form, more typically from 5 weight% to 60 weight % of the dosage form. In addition to the drug, tabletsgenerally contain a disintegrant. Examples of disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, crospovidone,polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose,lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinisedstarch and sodium alginate. Generally, the disintegrant will comprisefrom 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight% of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 weight % to 5 weight % of the tablet, and glidants may comprise from0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight %to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight %to about 90 weight % binder, from about 0 weight % to about 85 weight %diluent, from about 2 weight % to about 10 weight % disintegrant, andfrom about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

Consumable oral films for human or veterinary use are typically pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive and typically comprise a compound ofthe invention, a film-forming polymer, a binder, a solvent, a humectant,a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agentand a solvent. Some components of the formulation may perform more thanone function.

The compounds of the invention may be water-soluble or insoluble. Awater-soluble compound typically comprises from 1 weight % to 80 weight%, more typically from 20 weight % to 50 weight %, of the solutes. Lesssoluble compounds may comprise a greater proportion of the composition,typically up to 88 weight % of the solutes. Alternatively, the compoundsof the invention may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and is typically present in therange 0.01 to 99 weight %, more typically in the range 30 to 80 weight%.

Other possible ingredients include anti-oxidants, colorants, flavouringsand flavour enhancers, preservatives, salivary stimulating agents,cooling agents, co-solvents (including oils), emollients, bulkingagents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared byevaporative drying of thin aqueous films coated onto a peelable backingsupport or paper. This may be done in a drying oven or tunnel, typicallya combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Pharmaceutical Technology On-line,25(2), 1-14, by Verma et al (2001). The use of chewing gum to achievecontrolled release is described in WO 00/35298.

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally.

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μl to 100 μl. A typical formulation may comprisea compound of the invention, propylene glycol, sterile water, ethanoland sodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 0.001 mg to 10 mg of the compoundof the invention. The overall daily dose will typically be in the range0.001 mg to 40 mg which may be administered in a single dose or, moreusually, as divided doses throughout the day.

In another embodiment of the invention, the compounds of the inventionare preferably administered by inhalation. More preferably, thecompounds of the invention are administered by inhalation with a drypowder inhaler or a metered dose inhaler, most preferably with a drypowder inhaler.

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.

The compounds of the invention may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline.

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in International Patent Applications Nos. WO91/11172, WO 94/02518 and WO 98/55148.

In another embodiment of the invention, there is provided apharmaceutical composition comprising a compound of formula (I), or asalt and/or solvate thereof, and a pharmaceutically acceptable diluent,carrier or adjuvant.

In another aspect of the invention, there is provided a kit, including:

a. a compound of formula (I), or a salt and/or solvate thereof,

b. instructions for treating an obstructive or inflammatory airwaysdisease, and

c. packaging for containing a and b.

Preferably, the obstructive or inflammatory airways disease is COPD.

In an alternative embodiment, the instructions in b. are for treatingasthma.

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus another aspect of the invention is a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of the invention in accordance with the invention, and meansfor separately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention may be particularly suitable for administeringdifferent dosage forms, for example parenteral, for administering theseparate compositions at different dosage intervals, or for titratingthe separate compositions against one another. To assist compliance, thekit typically comprises directions for administration and may beprovided with a so-called memory aid.

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 0.01 mg to 10 mgdepending, of course, on the mode of administration. For example, aninhaled daily dose may only require from 0.01 mg to 5 mg. The totaldaily dose may be administered in single or divided doses and may, atthe physician's discretion, fall outside of the typical range givenherein.

These dosages are based on an average human subject having a weight ofabout 65 kg to 70 kg. The physician will readily be able to determinedoses for subjects whose weight falls outside this range, such asinfants and the elderly.

According to another embodiment of the present invention, the compoundsof the invention can also be used as a combination with one or moreadditional therapeutic agents to be co-administered to a patient toobtain some particularly desired therapeutic end result such as thetreatment of pathophysiologically-relevant disease processes including,but not limited to (i) bronchoconstriction, (ii) inflammation, (iii)allergy, (iv) tissue destruction, (v) signs and symptoms such asbreathlessness, cough. The second and more additional therapeutic agentsmay also be a compound of the invention, or one or more TNF inhibitorsand/or p38 inhibitors known in the art. More typically, the second andmore therapeutic agents will be selected from a different class oftherapeutic agents.

As used herein, the terms “co-administration”, “co-administered” and “incombination with”, referring to the compounds of the invention and oneor more other therapeutic agents, is intended to mean, and does refer toand include the following:

-   -   simultaneous administration of such combination of compound(s)        of the invention) and therapeutic agent(s) to a patient in need        of treatment, when such components are formulated together into        a single dosage form which releases said components at        substantially the same time to said patient,    -   substantially simultaneous administration of such combination of        compound(s) of the invention and therapeutic agent(s) to a        patient in need of treatment, when such components are        formulated apart from each other into separate dosage forms        which are taken at substantially the same time by said patient,        whereupon said components are released at substantially the same        time to said patient,    -   sequential administration of such combination compound(s) of the        invention and therapeutic agent(s) to a patient in need of        treatment, when such components are formulated apart from each        other into separate dosage forms which are taken at consecutive        times by said patient with a significant time interval between        each administration, whereupon said components are released at        substantially different times to said patient; and    -   sequential administration of such combination of compound(s) of        the invention and therapeutic agent(s) to a patient in need of        treatment, when such components are formulated together into a        single dosage form which releases said components in a        controlled manner whereupon they are concurrently,        consecutively, and/or overlappingly administered at the same        and/or different times by said patient, where each part may be        administered by either the same or different route.

Suitable examples of other therapeutic agents which may be used incombination with the compound(s) of the invention, or pharmaceuticallyacceptable salts, solvates or compositions thereof, include, but are byno means limited to:

-   (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating    protein (FLAP) antagonists,-   (b) Leukotriene antagonists (LTRAs) including antagonists of LTB₄,    LTC₄, LTD₄, and LTE₄,-   (c) Histamine receptor antagonists including H1 and H3 antagonists,-   (d) α₁- and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic    agents for decongestant use,-   (e) muscarinic M3 receptor antagonists or anticholinergic agents,-   (f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,-   (g) Theophylline,-   (h) Sodium cromoglycate,-   (i) COX inhibitors both non-selective and selective COX-1 or COX-2    inhibitors (NSAIDs),-   (j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated    agonists of the corticoid receptor)-   (k) Monoclonal antibodies active against endogenous inflammatory    entities,-   (l) β2 agonists, including long-acting 62 agonists-   (m) Adhesion molecule inhibitors including VLA-4 antagonists,-   (n) Kinin-B₁- and B₂-receptor antagonists,-   (o) Immunosuppressive agents,-   (p) Inhibitors of matrix metalloproteases (MMPs),-   (q) Tachykinin NK₁, NK₂ and NK₃ receptor antagonists,-   (r) Elastase inhibitors,-   (s) Adenosine A2a receptor agonists,-   (t) Inhibitors of urokinase,-   (u) Compounds that act on dopamine receptors, e.g. D2 agonists,-   (v) Modulators of the NFκB pathway, e.g. IKK inhibitors,-   (w) modulators of cytokine signalling pathways such as syk kinase,    or JAK kinase inhibitors,-   (x) Agents that can be classed as mucolytics or anti-tussive, and-   (y) Antibiotics.

According to the present invention, combination of the compounds of theinvention with:

-   -   H3 antagonists,    -   Muscarinic M3 receptor antagonists,    -   PDE4 inhibitors,    -   glucocorticosteroids,    -   Adenosine A2a receptor agonists,    -   β2 agonists    -   Modulators of cytokine signalling pathways such as syk kinase,        or,    -   Leukotriene antagonists (LTRAs) including antagonists of LTB₄,        LTC₄, LTD₄, and LTE₄, are preferred.

According to the present invention, combination of the compounds of theinvention with:

-   -   glucocorticosteroids, in particular inhaled glucocorticosteroids        with reduced systemic side effects, including prednisone,        prednisolone, flunisolide, triamcinolone acetonide,        beclomethasone dipropionate, budesonide, fluticasone propionate,        ciclesonide, and mometasone furoate and mometasone furoate        monohydrate,    -   muscarinic M3 receptor antagonists or anticholinergic agents        including in particular ipratropium salts, namely ipratropium        bromide, tiotropium salts, namely tiotropium bromide, oxitropium        salts, namely oxitropium bromide, perenzepine, and telenzepine,    -   or β2 agonists, in particular long-acting β2 agonists, including        salmeterol, formoterol, QAB-149 and CHF-4226.        are further preferred.

Preferably, the compounds of the invention exhibit slow-offset bindingkinetics to p38.

In another preferred embodiment, when the compounds are administered viathe inhalation route, they are rapidly metabolised when they have movedout of the lung.

More preferably, the compounds of the invention are metabolised tocompounds that are less active than the compound administered.

In another embodiment of the invention there is provided a compound,use, method or composition, substantially as described herein.

Assay: TNFα Screen

The anti-inflammatory properties of the compounds of the invention aredemonstrated by their ability to inhibit TNFα release from humanperipheral blood mononuclear cells. Venous blood is collected fromhealthy volunteers and the mononuclear cells purified by centrifugationthrough Histopaque (Ficoll) cushions. TNFα production from these cellsis stimulated by addition of lipopolysaccharide. After 18 hoursincubation in the presence of LPS, the cell supernatant is removed andthe concentration of TNFα in the supernatant determined by ELISA.Addition of the compounds of the invention reduces the amount of TNFαproduced. An IC₅₀ is determined which is equal to the concentration ofcompound that gives 50% inhibition of TNFα production as compared to theLPS stimulated control wells.

The examples were tested in the assay described above and were found tohave an IC₅₀ (TNFα screen) of less than 1000 nM, and for most of thetested compounds, were found to have an IC₅₀ (TNFα screen) of even lessthan 100 nM.

The examples tested were found to have an IC₅₀ (p38 assay) of less than1000 nM, and for most of the tested compounds, they were found to havean IC₅₀ (p38 assay) of even less than 100 nM.

In the present invention, the term “active”, “potent” or “potency” meansthat the compounds of formula (I) show TNF activity which is less than1000 nM as measured by the TNF assay described herein.

p38 Kinase Assay:

Cloning of Human p38a:

The coding region of the human p38a cDNA was obtained byPCR-amplification from RNA isolated from the human monocyte cell lineTHP.1. First strand CDNA was synthesized from total RNA as follows: 2 μgof RNA was annealed to 100 ng of random hexamer primers in a 10 μlreaction by heating to 70° C. for 10 minutes followed by 2 minutes onice. cDNA was then synthesized by adding 1 μl of RNAsin (Promega,Madison Wis.), 2 μl of 50 mM dNTP's, 4 μl of 5× buffer, 2 μl of 100 mMDTT and 1 μl (200 U) of Superscript II™ AMV reverse transcriptase.Random primer, dNTP's and Superscript II™ reagents were all purchasedfrom Life-Technologies, Gaithersburg, Mass. The reaction was incubatedat 42° C. for 1 hour. Amplification of p38 cDNA was performed byaliquoting 5 μl of the reverse transcriptase reaction into a 100 μl PCRreaction containing the following: 80 μl dH.sub.2O, 2 μl 50 mM dNTP's, 1μl each of forward and reverse primers (50 pmol/μl), 10 μl of 10× bufferand 1 μl Expand™ polymerase (Boehringer Mannheim). The PCR primersincorporated Bam HI sites onto the 5′ and 3′ end of the amplifiedfragment, and were purchased from Genosys. The sequences of the forwardand reverse primers were 5′-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3′ and5′GATCGAGGATTCTCAGGACTCCATCTCTTC-3′ respectively. The PCR amplificationwas carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 30cycles of 94° C. for 1 minute, 60° C. for 1 minute and 68° C. for 2minutes. After amplification, excess primers and unincorporated dNTP'swere removed from the amplified fragment with a Wizard™ PCR prep(Promega) and digested with Bam HI (New England Biolabs). The Bam HIdigested fragment was ligated into BamHI digested pGEX 2T plasmid DNA(PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) asdescribed by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nded. (1989). The ligation reaction was transformed into chemicallycompetent E. coli DH10B cells purchased from Life-Technologies followingthe manufacturer's instructions. Plasmid DNA was isolated from theresulting bacterial colonies using a Promega Wizard™ miniprep kit.Plasmids containing the appropriate Bam HI fragment were sequenced in aDNA Thermal Cycler (Perkin Elmer) with Prism™ (Applied Biosystems Inc.).cDNA clones were identified that coded for both human p38a isoforms (Leeet al. Nature 372, 739). One of the clones that contained the cDNA forp38a-2 (CSB-2) inserted in the cloning site of PGEX 2T, 3′ of the GSTcoding region was designated pMON 35802. The sequence obtained for thisclone is an exact match of the cDNA clone reported by Lee et al. Thisexpression plasmid allows for the production of a GST-p38a fusionprotein.

Expression of Human p38a

GST/p38a fusion protein was expressed from the plasmid pMON 35802 in E.coli, stain DH10B (Life Technologies, Gibco-BRL). Overnight cultureswere grown in Luria Broth (LB) containing 100 mg/ml ampicillin. The nextday, 500 ml of fresh LB was inoculated with 10 ml of overnight culture,and grown in a 2 liter flask at 37° C. with constant shaking until theculture reached an absorbance of 0.8 at 600 nm. Expression of the fusionprotein was induced by addition of isopropyl b-D-thiogalactosidase(IPTG) to a final concentration of 0.05 mM. The cultures were shaken forthree hours at room temperature, and the cells were harvested bycentrifugation. The cell pellets were stored frozen until proteinpurification.

Purification of P38 Kinase-Alpha

All chemicals were from Sigma Chemical Co. unless noted. Twenty grams ofE. coli cell pellet collected from five 1 L shake flask fermentationswas resuspended in a volume of PBS (140 mM NaCl, 2.7 mM KCl, 10 mMNa.sub.2 HPO.sub.4, 1.8 mM KH.sub.2 PO.sub.4, pH 7.3) up to 200 ml. Thecell suspension was adjusted to 5 mM DTT with 2 M DTT and then splitequally into five 50 ml Falcon conical tubes. The cells were sonnicated(Ultrasonics model W375) with a 1 cm probe for 3.times.1 minutes(pulsed) on ice. Lysed cell material was removed by centrifugation(12,000×g, 15 minutes) and the clarified supernatant applied toglutathione-sepharose resin (Pharmacia).

Glutathione-Sepharose Affinity Chromatography

Twelve ml of a 50% glutathione sepharose-PBS suspension was added to 200ml clarified supernatant and incubated batchwise for 30 minutes at roomtemperature. The resin was collected by centrifugation (600.times.g, 5min) and washed with 2.times.150 ml PBS/1% Triton X-100, followed by4.times.40 ml PBS. To cleave the p38 kinase from the GST-p38 fusionprotein, the glutathione-sepharose resin was resuspended in 6 ml PBScontaining 250 units thrombin protease (Pharmacia, specificactivity>7500 units/mg) and mixed gently for 4 hours at roomtemperature. The glutathione-sepharose resin was removed bycentrifugation (600.times.g, 5 min) and washed 2.times.6 ml with PBS.The PBS wash fractions and digest supernatant containing p38 kinaseprotein were pooled and adjusted to 0.3 mM PMSF.

Mono Q Anion Exchange Chromatography

The thrombin-cleaved p38 kinase was further purified by FPLC-anionexchange chromatography. Thrombin-cleaved sample was diluted 2-fold withBuffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5%glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchangecolumn equilibrated with Buffer A. The column was eluted with a 160 ml0.1 M-0.6 M NaCl/Buffer A gradient (2 ml/minute flowrate). The p38kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4ml with a Filtron 10 concentrator (Filtron Corp.).

Sephacryl S100 Gel Filtration Chromatography

The concentrated Mono Q-p38 kinase purified sample was purified by gelfiltration chromatography (Pharmacia HiPrep 26/60 Sephacryl S100 columnequilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT,5% glycerol)). Protein was eluted from the column with Buffer B at a 0.5ml/minute flowrate and protein was detected by absorbance at 280 nm.Fractions containing p38 kinase (detected by SDS-polyacrylamide gelelectrophoresis) were pooled and frozen at −80° C. Typical purifiedprotein yields from 5 L E. coli shake flasks fermentations were 35 mgp38 kinase.

Kinetics Assays

Association Kinetics:

SKF-86002 (from Calbiochem; KD ˜200 nM) gives an increase influorescence upon binding to p38a (as monitored by an excitation at 340nm and emission at 420 nm). SKF-86002 (1-2 uM) was preincubated withp38a (20-60 nM) for 5-10 min at room temperature in a buffer consistingof 20 mM Bis-Tris, 2 mM EDTA, 500 mM NaCl, 0.01% NaN3, 0.15% NOG and 5%DMSO. The sample compound (20-100 nM) was then added and the change influorescence monitored. As SKF dissociated from its binding site onp38a, the SKF was replaced by the sample compound and a decrease influorescence was observed on a time scale proportional to theassociation rate of the compound. Using the known binding kinetics ofSKF-86002, the association rate of the compound was measured.

Dissociation Kinetics:

Sample compounds (50 or 100 nM) were preincubated with p38a (37 nMprotein or 21 nM as determined by active site titration) overnight atroom temperature in a buffer consisting of 20 mM Bis-Tris, 2 mM EDTA,0.01% NaN3, 0.15% NOG, 500 mM NaCl and 5% DMSO. The following day, SKF86002 was added to a final concentration of 50 uM. The fluorescenceincrease observed upon the binding of SKF 86002 to p38a was monitored byexcitation at 340 nm and emission at 420 nm, and the dissociation ratewas measured.

Data:

The following data were generated using the TNF screen disclosed herein.

TNF IC50 Example nM 26 1.6 33 2.0 34 1.3 36 4.8 37 2.8 44 1.1 45 1.4 460.8 51 0.7 54 0.7 55 0.9 57 1.2 58 1.6 59 1.3 60 1.4 63 1.4 64 0.9 682.3 70 0.9 71 3.0 73 0.9 74 4.0 76 0.8 77 2.7 78 0.8 80 1.1 81 1.8 860.8 87 0.6 93 1.1 94 0.9 95 0.6 97 0.6 98 0.4 100 1.1 102 1.7 104 1.0105 0.6 109 1.2 114 3.6 116 3.2 118 15.7 124 4.6 125 80.0 128 3.7 1324.5 136 1.0 139 3.2 140 1.8 141 1.4 142 2.2 143 1.2 144 1.2 145 0.9 1511.4 152 4.9 153 4.8 179 1.5 180 21.0 181 2.7 182 0.7

EXAMPLES AND PREPARATIONS

Nuclear magnetic resonance (NMR) data were obtained using Varian UnityInova-400, Varian Unity Inova-300 or Bruker AC300 spectrometers and arequoted in parts per million from tetramethylsilane. Mass spectral (MS)data were obtained on a Finnigan Mat. TSQ 7000 or a Fisons InstrumentsTrio 1000. The calculated and observed ions quoted refer to the isotopiccomposition of lowest mass. For column chromatography on silica gel,Kieselgel 60, 230-400 mesh, from E. Merck, Darmstadt was used, unlessotherwise specified. Kieselgel 60 F₂₅₄ plates from E. Merck were usedfor TLC, and compounds were visualised using UV light, 5% aqueouspotassium permanganate or Dragendorff's reagent (oversprayed withaqueous sodium nitrite). Water content was determined on a MitsubishiCA100 (Coulometric Karl Fisher Titrator). Other measurements were takenusing standard equipment. PdCl₂(dppf).CH₂Cl₂ is1,1-bis(diphenylphosphino)ferrocene palladium (II) chloride 1:1dichloromethane complex.

DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene.

Preparation 1 2,2-Dimethyl-3-methylsulfanyl-propionic acid methyl ester

N,N-Diisopropylethylamine (15.5 g, 0.12 mol) was added to a solution ofmethyl 2,2-dimethyl-3-hydroxypropionate (13.2 g, 0.1 mol) indichloromethane (150 mL) and the solution was cooled to 0° C. Methanesulfonyl chloride (12.6 g, 0.11 mol) was then added dropwise and themixture was stirred at 0° C. for 90 minutes. The reaction mixture wasthen diluted with 0.5M hydrochloric acid (100 mL) and the layers wereseparated. The aqueous was extracted with dichloromethane (2×50 mL) andthe combined organic solution was dried over magnesium sulfate andconcentrated in vacuo. Methanethiol sodium salt (7.7 g, 0.11 mol) wasadded to a solution of the residue in dioxan (100 mL) and the mixturewas heated under reflux for 24 hours. The mixture was then diluted withethyl acetate (250 mL), washed with water and brine, dried overmagnesium sulfate and concentrated in vacuo. Purification by columnchromatography on silica gel, eluting with dichloromethane:pentane 50:50to 100:0, afforded the title compound as a pale yellow oil in 24% yield,3.85 g.

Preparation 2 4,4-Dimethyl-5-methylsulfanyl-3-oxo-pentanenitrile

A suspension of sodium hydride (60% dispersion in mineral oil, 1.20 g,30 mmol) in tetrahydrofuran (20 mL) was brought to reflux. A solution ofthe product of preparation 1 (3.84 g, 23.7 mmol) in acetonitrile (1.56mL, 30 mmol) was added and the mixture was heated under reflux for 3hours. The cooled reaction mixture was then diluted with water,acidified with 2M hydrochloric acid (30 mL) and extracted withdichloromethane (3×50 mL). The combined organic extracts were dried overmagnesium sulfate, concentrated in vacuo and the residue was purified bycolumn chromatography on silica gel, eluting with dichloromethane toafford the title compound as a pale yellow oil in 67% yield, 2.70 g.

Preparation 3 4-Methyl-4-methylsulfanyl-3-oxo-pentanenitrile

The title compound was prepared from ethyl2-methyl-2-(methylthio)propionate and acetonitrile, using a methodsimilar to that of preparation 2, as a colourless oil in 81% yield.

Preparation 4 (3-Methylsulfanyl-phenyl)-hydrazine

Magnesium turnings (0.79 g, 33 mmol) and a single crystal of iodine wereadded to a solution of 3-bromothioanilsole (6.11 g, 30 mmol) intetrahydrofuran (50 mL) and the mixture was stirred at room temperaturefor 18 hours. The mixture was cooled to −78° C. anddi-tertbutyldiazocarboxylate (6.91 g, 30 mmol) was added. The mixturewas stirred at −78° C. for 30 minutes and was then quenched by theaddition of 1M citric acid (40 mL). The reaction mixture was allowed towarm to room temperature and was extracted with ethyl acetate (250 mL).The organic solution was washed with brine and water, dried overmagnesium sulfate and concentrated in vacuo. The residue wasre-dissolved in isopropyl alcohol (200 mL) and the solution wassaturated with hydrogen chloride gas. The mixture was then allowed tocool to room temperature and was concentrated in vacuo. The residue wastaken up in water, basified with saturated sodium hydrogen carbonatesolution and extracted with dichloromethane:methanol, 90:10, (4×50 mL).The combined organic solution was dried over magnesium sulfateconcentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol,100:0 to 70:30, to afford the title compound as a dark orange liquid in36% yield.

Preparation 5 di-tert-Butyl1-(4-methoxy-3-methylphenyl)hydrazine-1,2-dicarboxylate

^(n)Butyllithium (2.5M in hexanes, 23.9 mL, 59.75 mmol) was added to asolution of 4-bromo-2-methylanisole (10 g, 49.74 mmol) intetrahydrofuran (150 mL) cooled to −78° C., and the mixture was stirredat this temperature for 1 hour. A solution ofdi-tert-butyldiazocarboxylate (13.74 g, 59.68 mmol) in tetrahydrofuran(50 mL) was then added dropwise and the mixture was stirred at −78° C.for one hour and then at room temperature for 2 hours. The reaction wasquenched with water (25 mL), concentrated in vacuo to low volume andpartitioned between diethyl ether (300 mL) and brine (300 mL). Theaqueous layer was separated and re-extracted with diethyl ether (2×100mL), and the combined organic solution was dried over sodium sulphateand concentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with heptanes:ethyl acetate,75:25, afforded the title compound as a pale yellow solid in 62% yield,10.93 g.

Preparation 6 (4-Methoxy-3-methylphenyl)hydrazine hydrochloride

4M Hydrochloric acid in 1,4-dioxane (37.5 mL, 150 mmol) was addeddropwise to a solution of the product of preparation 5 (10.75 g, 30.50mmol) in 1,4-dioxane (12.5 mL) and the mixture was stirred for 48 hoursat room temperature. The mixture was then concentrated in vacuo and theresidue was stirred in diethyl ether at 0° C. for 30 minutes. Theprecipitate was filtered off, washing through with diethyl ether, andthe solid was dried under vacuum at 40° C. for 6 hours to afford thetitle compound in 94% yield, 5.43 g.

Preparation 7 3-tert-Butyl-1-[4-(methylthio)phenyl]-1H-pyrazol-5-amine

Concentrated hydrochloric acid (1 mL) was added dropwise to a mixture of4-methylthiophenyl hydrazine (2 g, 10.5 mmol) and4,4-dimethyl-3-oxopentane nitrile (1.44 g, 11.5 mmol) in ethanol (30 mL)and the mixture was heated under reflux for 18 hours. The cooled mixturewas then diluted with ethyl acetate, washed with saturated sodiumhydrogen carbonate solution, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel, eluting with dichloromethane:methanol, 100:0 to 97:3 toafford the title compound as a yellow oil that crystallised on standing(2.59 g, 95% yield).

Preparations 8 to 19

The following compounds, of the general formula shown below wereprepared by a method similar to that described for preparation 7, usingthe appropriate hydrazine and nitrile starting materials. The reactionswere monitored by tlc analysis and were heated under reflux for 3-24hours.

No. X Y Data Yield

(Preps. 8-13) 8 SCH₃ H LRMS: m/z APCl 261 77% [MH]⁺ 9 Cl Cl LRMS: m/zAPCl 284 68% [MH]⁺ 10 H CO₂CH₂CH₃ LRMS: m/z APCl 288 55% [MH]⁺ 11CO₂CH₂CH₃ H LRMS: m/z APCl 288 28% [MH]⁺ 12 H CN m/z APCl 241 [MH]⁺ 52%13 CN H 58%

(preps. 14 and 15) 14 H CH₃ m/z APCl 276 [MH]⁺ 57% 15 H H m/z APCl 262[MH]⁺ 48%

(preps 16-19) 16 H H m/z APCl 248 [MH]⁺ 72% 17 O—CH₂Ph H m/z APCl 354[MH]⁺ 54% 18 H CF₃ m/z ES 316 [MH]⁺ 55% 19 H Cl m/z ES 282 [MH]⁺ 20%

Preparations 14-19: Purification achieved by column chromatography onsilica gel, eluting with dichloromethane:ethyl acetate. 80:20

Preparation 20 5-tert-Butyl-2-phenyl-2H-pyrazol-3-ylamine

N,N-Diisopropylethylamine (1.7 mL, 7.99 mmol) was added to a mixture ofphenyl hydrazine hydrochloride (1.5 g, 10.39 mmol) and4,4-dimethyl-3-oxopentane nitrile (1.0 g, 7.99 mmol) in ethanol (15 mL)and the mixture was heated under reflux for 18 hours. The cooled mixturewas then concentrated to low volume and partitioned between ethylacetate and saturated sodium hydrogen carbonate solution. The organiclayer was separated, dried over sodium sulfate and concentrated invacuo. The residue was purified by column chromatography on silica gel,eluting with heptanes:ethyl acetate, 75:25, to afford the title compoundas a pale orange oil that crystallised on standing (1.21 g, 70% yield).

Preparations 21 to 24

The following compounds, of the general formula shown below wereprepared by a method similar to that described for preparation 20, usingthe appropriate hydrazine and nitrile starting materials. The reactionswere monitored by tlc analysis and were heated under reflux for 3-24hours.

No. X Y Data Yield 21 H CH₃ LRMS: m/z API-ES 230.7 [MH]⁺ 79% 22 H O—CH₃LRMS: m/z API-ES 246.6 [MH]⁺ 58% 23 CH₃ OCH₃ LRMS: m/z API-ES 260 [MH]⁺84% 24 O—CH₃ H LRMS: m/z API-ES 246.7 [MH]⁺ 99%

Preparation 25 (5-Bromo-pyridin-2-yl)-hydrazine

2-Chloro-5-bromopyridine (64 g, 333 mmol) was suspended in hydrazinemonohydrate (250 mL) and the mixture was heated at 70° C. for 72 hours.The reaction mixture was then diluted with water (750 mL) and theresulting precipitate was filtered off and azeotroped, firstly withtoluene (×2) then dichloromethane (×2), to afford the title compound asa pale brown solid in 83% yield, 52 g.

Preparation 26 4-Chloro-3-hydroxymethyl-phenol

Lithium aluminium hydride (1M in diethyl ether, 25 mL, 25 mmol) wasadded to an ice-cooled solution of 2-chloro-5-hydroxy-benzoic acid (4 g,23.2 mmol) in tetrahydrofuran (200 mL) and the mixture was heated underreflux for 6 hours. The mixture was then diluted with a mixture ofwater/tetrahydrofuran, acidified with 1M hydrochloric acid, andextracted with ethyl acetate. The organic solution was dried over sodiumsulphate and concentrated in vacuo to afford the title compound inquantitative yield, 4.3 g.

Preparation 27 2-Chloro-5-hydroxy-benzaldehyde

Manganese dioxide (11 g, 125 mmol) was added to a suspension of theproduct of preparation 26 (4 g, 25.2 mmol) in acetone (25 mL) and themixture was heated to reflux for 3 hours. The reaction mixture was thencooled to room temperature and concentrated in vacuo. The residue wasdissolved in dichloromethane:methanol, 95:5, passed through a pad ofsilica and concentrated in vacuo to afford the title compound as a solidin 81% yield, 3.17 g

Preparation 28 2-Chloro-4-hydroxy-benzaldehyde

Diisobutylaluminium hydride (1M in hexane, 240 mL, 240 mmol) was addedto a solution of 2-chloro-4-hydroxybenzonitrile (15 g, 97.7 mmol) intetrahydrofuran (200 mL), cooled to −78° C., and the mixture was stirredat this temperature for 1 hour then at room temperature for 18 hours.The mixture was then cooled to 0° C. and 1M hydrochloric acid (80 mL)was added dropwise. The reaction mixture was diluted with water (200 mL)and filtered, washing through with ethyl acetate (×2). The layers of thefiltrate were separated and the organic solution was dried overmagnesium sulfate and concentrated in vacuo, Trituration of the residuewith dichloromethane afforded the title compound as a solid in 84%yield, 12.92 g.

Preparation 29 Isobutyric acid N′-(5-bromo-pyridin-2-yl)-hydrazide

N,N-Diisopropylethylamine (137 g, 1.06 mol) was added to a suspension ofthe product of preparation 25 (40 g, 213 mmol) in dichloromethane (100mL) and the solution was cooled to 0° C. Isobutyryl chloride (22.7 g,213 mmol) was then added dropwise and the mixture was stirred at 0° C.for 2 hours. The reaction mixture was quenched with water and theresulting solid was filtered off and dried for 48 hours in air. Thesolid was then re-crystallised from methanol/N,N-diisopropylethylamine,25:75, to afford the title compound as a white crystalline solid in 85%yield, 1.16 g.

Preparation 30 2-(Benzyloxy)benzaldehyde(5-bromopyridin-2-yl)hydrazone

A mixture of 2-benzyloxybenzaldehyde and the product of preparation 25(10 g, 53.2 mmol) in ethanol (350 mL) was heated at 80° C. for 15minutes. The resulting precipitate was filtered off, washing throughwith ethanol, and dried under vacuum for 18 hours to afford the titlecompound as a white solid in 94% yield.

Preparation 31 6-Bromo-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine

A suspension of the product of preparation 29 (16 g, 62 mmol) inphosphorus oxychloride (320 mL) was heated at 75° C. for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue wasdissolved in water, basified with 2M sodium hydroxide solution andextracted with ethyl acetate. The organic solution was dried over sodiumsulfate and concentrated in vacuo. Trituration of the residue in ethylacetate/methanol, 98:2, afforded the title compound in 75% yield, 11.23g.

Preparation 323-(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-chloro-phenol

A mixture of the product of preparations 27 (3.1 g, 19.7 mmol) and 25(3.7 g, 19.7 mmol) in ethanol (75 mL) was heated under reflux for 1hour. The mixture was then cooled to room temperature, diluted withethanol (75 mL) and iodobenzene diacetate (6.30 g, 19.7 mmol) was added.The reaction mixture was then stirred at room temperature for 18 hours.The mixture was concentrated in vacuo, triturated with a mixture ofethyl acetate and methanol and filtered off. The residue was furtherpurified by column chromatography on silica gel, eluting withdichloromethane:methanol, 90:10, to afford the title compound in 15%yield, 0.95 g

Preparation 334-(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-chloro-phenol

The title compound was prepared from the products of preparations 28 and25, using a method similar to that of preparation 32, as a solid in 78%yield.

Preparation 343-[2-(Benzyloxy)phenyl]-6-bromo[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 30,using a similar method to preparation 33. The title compound was furtherpurified by column chromatography on silica gel, eluting with ethylacetate:dichloromethane, 50:50, followed by trituration with diethylether/ethyl acetate to afford the title compound as a solid in 88%yield.

Preparation 35[2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-phenyl]-methanol

2-Mercaptobenzyl alcohol (12.8 g, 91 mmol) was added to a mixture of theproduct of preparation 31 (19.8 g, 70 mmol), cesium carbonate (31.9 g,98 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II)dichloromethane adduct (5.7 g, 7.0 mmol) in N,N-dimethylformamide (175mL) and the reaction mixture was heated to 90° C. for 21 hours. Themixture was then cooled, diluted with water and extracted with ethylacetate. The organic solution was dried over sodium sulfate,concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with ethyl acetate:methanol, 98:2,and triethylamine (one drop per 100 mL of organic solution), to affordthe title compound as a brown solid in 33% yield, 7 g.

Preparation 364-Chloro-3-(6-{[2-(hydroxymethyl)phenyl]thio}[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenol

The title compound was prepared from the product of preparation 32 and2-mercaptobenzyl alcohol, using a method similar to that of preparation35, as a pale brown solid in 62% yield.

Preparation 373-Chloro-4-(6-{[2-(hydroxymethyl)phenyl]thio}[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenol

The title compound was prepared from the product of preparation 33 and2-mercaptobenzyl alcohol, using a method similar to that of preparation35, as a pale brown foam in 41% yield.

Preparation 38[2-({3-[2-(Benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)phenyl]methanol

The title compound was prepared from the product of preparation 34 and2-mercaptobenzyl alcohol, using a method similar to that of preparation35, as a brown solid in 57% yield.

Preparation 396-(2-Azidomethyl-phenylsulfanyl)-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine

1,8-Diazabicyclo[5.4.0]undec-7-ene (6.4 g, 42.1 mmol) was added to anice-cold suspension of the product of preparation 35 (10.5 g, 35.1 mmol)and diphenylphosphoryl azide (11.6 g, 42.1 mmol) in toluene (60 mL) andthe mixture was stirred at 0° C. for 3 hours and at room temperature for18 hours. The reaction was then quenched with sodium hydrogen carbonatesolution and extracted with ethyl acetate. The organic solution waswashed with brine, dried over sodium sulfate and concentrated in vacuo.Purification by column chromatography on silica gel, eluting with ethylacetate:methanol, 98:2, and triethylamine (one drop per 100 mL oforganic solution), then afforded the title compound as a brown oil in79% yield, 9 g.

Preparation 403-(6-{[2-(Azidomethyl)phenyl]thio}[1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-chlorophenyldiphenyl phosphate

The title compound was prepared from the product of preparation 36,using a method similar to that of preparation 39, in 84% yield.

Preparation 414-(6-{[2-(Azidomethyl)phenyl]thio}[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-chlorophenol

The title compound was prepared from the product of preparation 37,using a method similar to that of preparation 39, as a pale brown foamin 58% yield.

Preparation 426-{[2-(azidomethyl)phenyl]thio}-3-[2-(benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 38,using a method similar to that of preparation 39, as a liquid in 45%yield.

Preparation 43{2-[(3-Isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}aminehydrochloride

Triphenylphosphine (10.6 g, 40.3 mmol) and water (0.73 mL, 40.3 mmol)were added to a solution of the product of preparation 39 (10.8 g, 33.6mmol) in tetrahydrofuran (114 mL) and the mixture was stirred at roomtemperature for 40 hours, then warmed to 40° C. for 5 hours. Thereaction mixture was then cooled to room temperature, diluted with waterand extracted with ethyl acetate. The organic solution was washed withbrine, dried over sodium sulfate and concentrated in vacuo. The residuewas dissolved in dichloromethane and cooled in an ice-bath. 1MHydrochloric acid in diethyl ether (35 mL) was added dropwise and themixture was stirred for 18 hours at room temperature. The resultingprecipitate was filtered off and dried over phosphorus pentoxide toafford the title compound as a grey solid in 65% yield, 7.24 g.

Preparation 443-(6-{[2-(Aminomethyl)phenyl]thio}[1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-chlorophenolhydrochloride

The title compound was prepared from the product of preparation 40,using a method similar to that of preparation 43. The crude product wasre-dissolved in methanol and saturated with 1M hydrochloric acid indiethyl ether to afford the desired product in quantitative yield.

Preparation 454-(6-{[2-(Aminomethyl)phenyl]thio}[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-chlorophenolhydrochloride

The title compound was prepared from the product of preparation 41,using a method similar to that of preparation 43. The crude product wasre-dissolved in methanol and saturated with 1M hydrochloric acid indiethyl ether to afford the desired product in 60% yield.

Preparation 46[2-({3-[2-(benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-aminehydrochloride

The title compound was prepared from the product of preparation 42,using a method similar to that of preparation 43. The crude product wasre-dissolved in methanol and saturated with 1M hydrochloric acid indiethyl ether to afford the desired product as a white solid in 78%yield.

Preparation 47 4,4-Dimethyl-3-oxohexanenitrile

A suspension of sodium hydride (60% dispersion in mineral oil, 3.18 g,79.4 mmol) in tetrahydrofuran (60 mL) was heated at 60° C. for 1 hour.The reaction mixture was then cooled to room temperature, acetonitrile(4.2 mL, 79.4 mmol) and 2,2-dimethyl-butyric acid ethyl ester [(7.95 g,61 mmol), J. Am. Chem. Soc., 1942, 64, 2964] in tetrahydrofuran (100 mL)were added and the mixture was stirred for 4 hours at 25° C. The mixturewas then diluted with 1M hydrochloric acid (100 mL) and the aqueouslayer was separated and extracted with ethyl acetate. The organicsolution was then dried over magnesium sulfate, concentrated in vacuoand the residue was triturated with heptane to afford the title compoundas a pale brown solid in 27% yield, 2.3 g.

Preparation 48 1-(Benzyloxy)-3-bromo-5-methylbenzene

A mixture of 3-bromo-5-methylphenol [(40.7 g, 218 mmol) J. Amer. Chem.Soc., 2003, 125, 7792)], benzyl bromide (28.6 mL, 239 mmol) andpotassium carbonate (90.2 g, 653 mmol) in acetone (1 L) was heated underreflux for 2 hours. The cooled reaction mixture was then acidified with2M hydrochloric acid and the aqueous layer was extracted with ethylacetate. The organic solution was washed with brine (×3), dried overmagnesium sulfate and concentrated in vacuo to afford the title compoundas a red oil in quantitative yield.

Preparation 49 Benzyl 5-(benzyloxy)-2-chlorobenzoate

The title compound was prepared from 2-chloro-5-hydroxybenzoic acid(US2002/0037905 p15), using a similar method to that described forpreparation 46, as an oil in quantitative yield.

Preparation 50 4-(Benzyloxy)-2-chlorobenzonitrile

Potassium carbonate (66.3 g, 480 mmol) was added to a mixture of2-chloro-4-hydroxybenzonitrile (25 g, 160 mmol) and benzyl bromide (19.3mL, 161 mmol) in acetonitrile (300 mL) and the mixture was stirred for18 hours at room temperature. The reaction mixture was then filtered andthe filtrate was concentrated in vacuo. Trituration of the residue withheptanes afforded the title compound as an off-white solid in 99% yield,38.65 g.

Preparation 51 4-(Benzyloxy)-2-chlorobenzaldehyde

The title compound was prepared from the product of preparation 50,using the same method as that described for preparation 28, in 97%yield.

Preparation 52 4-Bromo-1-ethyl-2-methoxybenzene

Methyl iodide (3 mL, 47.3 mmol) was added to a solution of4-bromo-2-hydroxyacetophenone (9.25 g, 43 mmol) and potassium carbonate(6.54 g, 47.3 mmol) in acetone (20 mL) and the mixture was stirred atroom temperature for 18 hours. The reaction mixture was concentrated invacuo to low volume and diluted with water. The aqueous mixture wasextracted with dichloromethane (3×50 mL) and the combined organicsolution was washed with water, dried over sodium sulfate andconcentrated in vacuo. The residue was dissolved in 1,2-ethanediol (10mL), hydrazine (19.47 mL, 400 mmol) and potassium hydroxide (7.86 g, 140mmol) were added and the reaction mixture was heated at 150° C. for 60hours. The reaction mixture was then quenched with 1M hydrochloric acidand extracted with ethyl acetate (3×20 mL). The combined organicsolution was dried over sodium sulfate, concentrated in vacuo and theresidue was purified by Kugel Rohr fractional distillation (150° C./0.05mbar) to provide the title compound as a yellow oil (128 mg).

Preparation 53N-(3-Chloro-4-methoxyphenyl)-N′-(2,2-dimethylpropanoyl)-2,2-dimethylpropanohydrazide

The title compound was prepared from 4-bromo-2-chloro-1-methoxy-benzene(J. Org. Chem. 1982, 47, 5270) and di-tert-butyldiazocarboxylate, usingthe same method as that of preparation 5, as a white powder in 43%yield.

Preparation 54 di-tert-Butyl1-[3-(benzyloxy)-5-methylphenyl]hydrazine-1,2-dicarboxylate

The title compound was prepared from the product of preparation 48 anddi-tert-butyldiazocarboxylate, using the same method as that describedfor preparation as that of preparation 5, as a yellow liquid in 84%yield.

Preparation 55 di-tert-butyl1-(3-ethyl-4-methoxyphenyl)hydrazine-1,2-dicarboxylate

The title compound was prepared from 4-bromo-2-ethyl-1-methoxy-benzeneand di-tertbutyldiazocarboxylate, using the same method as thatdescribed for preparation 53, as a solid in 53% yield.

Preparation 56 di-tert-Butyl1-(4-ethyl-3-methoxyphenyl)hydrazine-1,2-dicarboxylate

The title compound was prepared from the product of preparation 52 anddi-tert-butyldiazocarboxylate, using the same method as that describedfor preparation 53, as a pale yellow oil in 40% yield.

Preparation 57 (3-Chloro-4-methoxyphenyl)hydrazine hydrochloride

The title compound was prepared from the product of preparation 53,using the same method as that described for preparation 6, as anoff-white powder in 93% yield.

Preparation 58 [3-(Benzyloxy)-5-methylphenyl]hydrazine hydrochloride

The title compound was prepared from the product of preparation 54,using the same method as that described for preparation 6, as a solid in59% yield.

Preparation 59 (3-Ethyl-4-methoxyphenyl)hydrazine hydrochloride

The title compound was prepared from the product of preparation 55,using the same method as that described for preparation 6, as a solid inquantitative yield.

Preparation 60 (4-Ethyl-3-methoxyphenyl)hydrazine hydrochloride

The title compound was prepared from the product of preparation 56,using the same method as that described for preparation 6, as anoff-white solid in 85% yield.

Preparations 61 to 86, 88 and 89

The following compounds, of the general formula shown below wereprepared by a method similar to that described for preparation 7, usingthe appropriate commercially available hydrazine and commerciallyavailable nitrile starting materials. Where the starting materials arenot commercially available, the syntheses are disclosed herein. Thereactions were monitored by tlc analysis and were heated under refluxfor 3-24 hours.

No. Data Yield A = C(CH₃)₃ 61 X = 4-F 57% 62 X = 3-F 94% 63 X = 3-OCH₂Ph90% 64 X = 4-CH₂CH₃ 91% 65 X = 3-CH₂CH₃ 78% 66 X = 3-OCH₂Ph, 5-CH₃ 60%67 X = 4-OCH₃ 49% 68 X = 3-OCH₃ 86% 69 X = 3-OCH₃, 4-Cl 50% A = (CH₂CH₃)C(CH₃)₂ 70 X = 3-OCH₂Ph 91% 71 X = 4-CH₃ 35% A = (CH₃—S—CH₂)C(CH₃)₂72 X = 3-OCH₂Ph 71% 73 X = 4-F 35% 74 X = 3-F 75% 75 X = 3-F, 4-F 63% 76X = 4-OCH₂Ph 70% A = (CH₃—S)C(CH₃)₂ 77 X = 3-CF₃ 73% 78 X = 4-F 62% 79 X= 3-F 86% 80 X = 3-Cl 50% 81 X = 3-F, 4-F 79% 82 X = 4-CH₂CH₃ 79% 83 X =3-CH₂CH₃ 65% 84 X = 3-CH₃, 4-OCH₃ 25% 85 X = 4-CH₃ 50% 86 X = 3-CH₃quant 88 X = 3-Br 52% 89 X = 3-CH₃, 5-CH₃ 73% ^(o) Crude compounds werepurified by column chromatography on silica gel, eluting withheptanes:ethyl acetate, 75:25

Preparation 83: was prepared from the product of preparation 3 and(3-ethylphenyl)-hydrazine hydrochloride (EP 177242, p31)

Preparation 84: crude compound was purified by column chromatography onsilica gel, eluting with pentane:ethyl acetate, 100:0 to 60:40.

Preparation 86: crude compound was purified by column chromatography onsilica gel, eluting with hexane:ethyl acetate, 91:9 to 83:17.

Preparation 87 (4-Chloro-3-methoxyphenyl)hydrazine

Concentrated hydrochloric acid (12 mL) and a solution of sodium nitrite(1.7 g, 24.4 mmol) in water (8 mL) were added to a solution of4-chloro-3-methoxy aniline (3.86 g, 24.4 mmol) in water (8 mL), at −10°C. The mixture was stirred for 30 minutes and was then added to solutionof tin chloride (14.89 g, 66 mmol) in concentrated hydrochloric acid (24mL) and water (24 mL), cooled to 0° C. The reaction mixture was stirredfor 18 hours, allowing the temperature to rise to 25° C. The resultingprecipitate was filtered off and the solid was re-crystallised fromheptanes/ethyl acetate (33:66) to afford the title compound the titlecompound as white solid in 72% yield, 3 g

Preparation 90 3-tert-Butyl-1-pyridin-3-yl-1H-pyrazol-5-amine

The title compound was prepared from 4,4-dimethyl-3-oxopentane nitrileand 3-pyridinohydrazide (US2002/0143176, p22), using the same method asthat described for preparation 7, as an orange oil in 50% yield.

Preparation 91 3-tert-Butyl-1-pyridin-2-yl-1H-pyrazol-5-amine

The title compound was prepared from 4,4-dimethyl-3-oxopentane nitrileand 2-hydrazinopyridine, using the same method as that described forpreparation 7, as a solid in 99% yield.

Preparation 921-[4-(benzyloxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-amine

Concentrated hydrochloric acid (2 mL) was added dropwise to a suspensionof [4-(benzyloxy)phenyl]hydrazine hydrochloride (3.19 g, 12.74 mmol) andthe product of preparation 3 (2 g, 12.74 mmol) in ethanol (50 mL) andthe mixture was heated under reflux for 2 hours. Water was then added (5mL) and the reaction mixture was heated under reflux for a further 16hours. The cooled mixture was then diluted with ethyl acetate, washedwith saturated sodium hydrogen carbonate solution, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography on silica gel, eluting with dichloromethane:ethylacetate, 100:0 to 85:15, to afford the title compound as an orange oilthat crystallised on standing (2.79 g, 62% yield).

Preparations 93 to 97

The following compounds, of the general formula shown below wereprepared by a method similar to that described for preparation 20, usingthe appropriate commercially available hydrazine and commerciallyavailable nitrile starting materials. Where the starting materials arenot commercially available, the syntheses are disclosed herein. Thereactions were monitored by tlc analysis and were heated under refluxfor 3-24 hours.

No. Data Yield A = C(CH₃)₃ 93 X = 4-CH₃ 57% 94 X = 3-Cl, 4-OCH₃ 48% 95 X= 3-F, 4-F 18% 96 X = 3-CH₂CH₃, 4-OCH₃ 65% 97 X = 3-OCH₃, 4-CH₂CH₃ 27%Preparation 93: The crude compound was triturated with heptane: diethylether 66:33.

Preparation 98 [4-(5-Amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]methanol

Lithium aluminium hydride (1M in tetrahydrofuran, 1.83 mL, 1.83 mmol)was added to an ice-cold solution of4-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-yl]-benzoic acid methylester [(0.25 g, 0.92 mmol), WO2004060306, p134] in tetrahydrofuran (5mL), and the mixture was stirred at 0° C. for 1 hour. The reaction wasthen quenched with water (0.35 mL) and 1M sodium hydroxide solution(0.35 mL) followed by further water (1 mL). The mixture was thenextracted with diethyl ether, (10 mL) and the organic solution was driedover sodium sulfate and concentrated in vacuo to afford the titlecompound as red oil in 98% yield, 220.1 mg.

Preparation 993-tert-Butyl-1-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-1H-pyrazol-5-amine

A mixture of the product of preparation 98 (0.5 g, 2.04 mmol),tert-butyldimethylsilyl chloride (0.34 g, 2.25 mmol) and imidazole (0.18g, 2.55 mmol) in N,N-dimethylformamide (2 mL) was stirred at roomtemperature for 18 hours. The reaction mixture was then diluted withmethanol (1 mL) and stirred for 15 minutes at room temperature. Themixture was diluted further with sodium hydrogen carbonate solution (20mL) and extracted with ethyl acetate (3×15 mL). The combined organicsolution was dried over sodium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith heptanes:ethyl acetate, 85:15, 75:25, to afford the title compoundas a colourless solid in 30% yield, 220.5 mg.

Preparation 1003-tert-Butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylphenyl)-1H-pyrazol-5-amine

The title compound was prepared from5-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-1-yl]-2-methylphenolhydrochloride (WO 03/005999, p81-p82) and tert-butyldimethylsilylchloride, using the same method as that described for preparation 99, asa solid in 86% yield.

Preparation 101 3-(5-Amino-3-tert-butyl-1H-pyrazol-1-yl)phenol

Boron tribromide (1M in dichloromethane, 12 mL, 12 mmol) was addeddropwise to an ice-cold solution of the product of preparation 63 (1.28g, 4 mmol) in dichloromethane (50 mL) and the mixture was stirred for 30minutes, allowing the temperature to rise to 25° C. The reaction mixturewas then diluted with methanol (20 mL) and water, basified with 0.88ammonia and extracted with dichloromethane (3×50 mL). The combinedorganic solution was dried over magnesium sulfate concentrated in vacuoand the residue was purified by column chromatography on silica gel,eluting with dichloromethane:ethyl acetate, 100:0 to 80:20, to affordthe title compound as a pale yellow foam in 89% yield, 825 mg.

Preparation 1024-{5-Amino-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-1-yl}phenol

The title compound was prepared from the product of preparation 76,using a similar method to that described for preparation 101, as a whitesolid in 40% yield.

Preparation 103N-{1-[4-(Benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}benzamide

The title compound was prepared from the product of 244 and phenylchloroformate, using the same method as that described for preparation116, as a brown oil in quantitative yield.

Preparation 1041-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 102 andtert-butyldimethylsilyl chloride, using the same method as thatdescribed for preparation 99, as a yellow oil in 48% yield.

Preparation 105

1-(3-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 110 andtert-butyldimethylsilyl chloride, using the same method as thatdescribed for preparation 99, as a red oil in 49% yield.

Preparation 1063-tert-Butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 101 andtert-butyldimethylsilyl chloride using the same method as that describedfor preparation 99, as a colourless oil in 34% yield.

Preparation 1073-{5-Amino-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-1-yl}-phenol

The title compound was prepared from the product of preparation 72,using the same method as that described for preparation 101, as a yellowsolid in 18% yield.

Preparation 1083-[5-Amino-3-(1,1-dimethylpropyl)-1H-pyrazol-1-yl]-phenol

A solution of boron tribromide (1.7 mL, 17.9 mmol) in dichloromethane(20 mL) was added dropwise to an ice-cold solution of the product ofpreparation 70 (1.20 g, 3.6 mmol) in dichloromethane (15 mL) and themixture was stirred for 90 minutes, allowing the temperature to rise to25° C. Dimethylamine (40% in water, 5 mL) was then added dropwise andthe mixture was stirred for 1 hour at room temperature. The aqueouslayer was separated, extracted with ethyl acetate and the organicsolution was dried over magnesium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with heptanes:ethyl acetate, 100:0 to 50:50, afforded the titlecompound as a yellow foam in 49% yield, 390 mg.

Preparation 1092-(6-{[2-(Aminomethyl)phenyl]thio}[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenol

The product of preparation 46 (3.43 g, 7.22 mmol) was suspended inhydrobromic acid (5.7M in glacial acetic acid, 7 mL, 40 mmol) and themixture was stirred at room temperature for 18 hours. The reactionmixture was diluted with diethyl ether (150 mL), stirred at roomtemperature for 15 minutes and then filtered off. The residue waspartitioned between dichloromethane and saturated sodium hydrogencarbonate solution and the resulting precipitate was filtered off andre-dissolved in dichloromethane:methanol, (90:10, 400 mL), The aqueouslayer of the filtrate was separated and extracted three times withdichloromethane:methanol, (90:10). The extracts were then combined withthe solution of dissolved residue, dried over magnesium sulfate andconcentrated in vacuo. Trituration of the residue with diethyl etherafforded the title compound as a solid in 96% yield, 2.40 g.

Preparation 1103-{5-Amino-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-1-yl}phenol

The title compound was prepared from the product of preparation 87,using the same method as that described for preparation 109, as a whitefoam in 44% yield.

Preparation 1113-tert-Butyl-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-amine

A mixture of the product of preparation 101 (750 mg, 3.25 mmol),2-(2-bromoethoxy)tetrahydro-2H-pyran (1.02 g, 4.88 mmol) and potassiumcarbonate (690 mg, 5 mmol) in N,N-dimethylformamide (10 mL) was stirredat 60° C. for 4 hours. The reaction mixture was then cooled to roomtemperature diluted with ethyl acetate and washed with water (×2) andbrine. The organic solution was then dried over magnesium sulfate,concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:ethylacetate, 100:0 to 85:15, to afford the title compound as a yellow oil in71% yield.

Preparation 1123-[1-Methyl-1-(methylthio)ethyl]-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 110 and2-(2-bromoethoxy)tetrahydro-2H-pyran, using the same method as thatdescribed for preparation 111, as an orange oil in 94% yield.

Preparation 1133-[1,1-Dimethyl-2-(methylthio)ethyl]-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 107 and2-(2-bromoethoxy)tetrahydro-2H-pyran, using the same method as thatdescribed for preparation 111, as a yellow oil in 71% yield.

Preparation 1143-(1,1-Dimethylpropyl-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 108 and2-(2-bromoethoxy)tetrahydro-2H-pyran, using the same method as thatdescribed for preparation 111, as a yellow oil in 71% yield.

Preparation 1153-[1-Methyl-1-(methylthio)ethyl]-1-{4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 102 and2-(2-bromoethoxy)tetrahydro-2H-pyran, using the same method as thatdescribed for preparation 111, as a yellow oil in 82% yield.

Preparation 116Phenyl(3-tert-butyl-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)carbamate

Phenylchloroformate (1.94 g, 12.4 mmol) was added to an ice-cooledsolution of the product of preparation 111 (4.05 g, 11.3 mmol) andpyridine (1.09 mL, 13.5 mmol) in tetrahydrofuran (50 mL) and the mixturewas stirred at 0° C. for 5 minutes and at room temperature for 20minutes. The reaction mixture was then diluted with ethyl acetate,washed with water, 5% citric acid and saturated sodium hydrogencarbonate solution, dried over magnesium sulfate and concentrated invacuo to afford the title compound as a yellow oil in 86% yield, 5.22 g.

Preparation 117 Phenyl(3-[1-methyl-1-(methylthio)ethyl]-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)carbamate

The title compound was prepared from the product of preparation 112 andphenylchloroformate, using the same method as that described forpreparation 116, as an orange oil in quantitative yield.

Preparation 118 Phenyl{1-[3-(benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}carbamate

The title compound was prepared from the product of preparation 63 andphenylchloroformate, using the same method as that described forpreparation 116, as a brown solid in 94% yield.

Preparation 119Phenyl[3-tert-butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-yl]-carbamate

The title compound was prepared from the product of preparation 106 andphenylchloroformate, using the same method as that described forpreparation 116, as a clear oil in quantitative yield.

Preparation 120 Phenyl{1-(3-{[tertbutyl(dimethyl)silyl]oxy}phenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}carbamate

The title compound was prepared from the product of preparation 105 andphenylchloroformate, using the same method as that described forpreparation 116, as a red oil in quantitative yield.

Preparation 121N-[2-({3-2-(benzyloxy)phenyl[1,2,4]triazolo[4,3-a]pyridine-6-yl}thio)benzyl]-N′-[3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl]urea

The product of preparation 61 (117 mg, 0.50 mmol) was added to asolution of N,N′-carbonyldiimidazole (405 mg, 2.50 mmol) indichloromethane (20 mL) and the mixture was stirred at room temperaturefor 16 hours. The reaction mixture was then diluted with water andextracted with dichloromethane (3×20 mL). The combined organic solutionwas dried over magnesium sulfate and concentrated in vacuo. The productof preparation 46 (142 mg, 0.30 mmol) was added to a solution of theresidue and N-ethyldiisopropylamine (129 mg, 1 mmol) in dichloromethane(10 mL) and the mixture was stirred for 45 minutes at room temperature.The reaction mixture was then diluted with ethyl acetate, washed with0.5M hydrochloric acid and brine, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel, eluting with ethyl acetate:methanol, 100:0 to 90:10, toafford the title compound as a glass in 90% yield, 189 mg.

Preparation 122N-[2-({3-2-(benzyloxy)phenyl[1,2,4]triazolo[4,3-a]Pyridine-6-yl}thio)benzyl]-N′-(3-tert-butyl-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)urea

The product of preparation 111 (180 mg, 0.50 mmol) was added to asolution of N,N′-carbonyldiimidazole (405 mg, 2.50 mmol) indichloromethane (20 mL) and the mixture was stirred at room temperaturefor 18 hours. The reaction mixture was then diluted with water andextracted with dichloromethane (3×20 mL). The combined organic solutionwas dried over magnesium sulfate and concentrated in vacuo. The productof preparation 46 (167 mg, 0.35 mmol) was added to a solution of theresidue and N-ethyldiisopropylamine (0.17 mL, 1 mmol) in dichloromethane(10 mL) and the mixture was stirred for 1 hour at room temperature. Thereaction mixture was then diluted with ethyl acetate, washed with 0.1Ncitric acid and brine, dried over magnesium sulfate and concentrated invacuo. The residue was purified by column chromatography on silica gel,eluting with ethyl acetate:methanol, 95:5, to afford the title compoundin 95% yield, 273 mg.

Preparations 123 to 166

The following compounds, of the general formula shown below wereprepared by a method similar to that described for preparation 121,using the appropriate amine, N,N′-carbonyldiimidazole and theappropriate aminopyrazole starting materials, which are available fromthe syntheses disclosed herein or are commercially available. Thereactions were monitored by tlc analysis and were stirred at roomtemperature for 20-72 hours.

No. Data Yield A = C(CH₃)₃ 123 X = 3-(benzyloxy)phenyl, R³ =2-hydroxyphenyl 72% 124 X = 4-CH₃; R³ = 2-(benzyloxy)phenyl 82% 125 X =3-CH₃; R³ = 2-(benzyloxy)-5-chlorophenyl 78% 126 X = 4-CH₂CH₃; R³ =2-(benzyloxy)phenyl 80% 127 X = 3-CH₂CH₃; R³ = 2-(benzyloxy)phenyl 86%128 X = 3-Cl, 4-Cl; R³ = 2-(benzyloxy)phenyl 73% 129 X = 3-CN; R³ =2-(benzyloxy)phenyl 87% 130 X = 4-CN; R³ = 2-(benzyloxy)phenyl 58% 131 X= H; R³ = 2-(benzyloxy)phenyl 77% 132 X = 3-OCH₂Ph; 5-CH₃; R³ = HC(CH₃)₂48% 133 X = 3-CH₂CH₃, 4-OCH₃; R³ = HC(CH₃)₂ 42% 134 X = 3-OCH₃,4-CH₂CH₃; R³ = HC(CH₃)₂ 17% 135 X = 3-F, 4-F; R³ = 2-(benzyloxy)phenyl34% 136 X = 4-({[tert-butyl(dimethyl)silyl]oxy}methyl); 58% R³ =HC(CH₃)₂ 137 X = 3-{[tert-butyl(dimethyl)silyl]oxy}, 66% 4-CH₃; R³ =HC(CH₃)₂ 138 X = 4-OCH₃; R³ 2-(benzyloxy)phenyl 84% 139 X = 3-OCH₃; R³2-(benzyloxy)phenyl 69% 140 X = 3-OCH₃, 4-Cl; R³ = HC(CH₃)₂ 58% A =(CH₃—CH₂)C(CH₃)₂ 141 X = 4-CH₃; R³ = 2-(benzyloxy)phenyl 36% A =(CH₃—S—CH₂)C(CH₃)₂ 142 X = H; R³ = 2-(benzyloxy)phenyl 86% 143 X =4-CH₃; R³ = 2-(benzyloxy)phenyl 78% 144 X = 4-F; R³ =2-(benzyloxy)phenyl 77% 145 X = 3-F; R³ = 2-(benzyloxy)phenyl 78% 146 X= 3-F, 4-F; R³ = 2-(benzyloxy)phenyl 44% 147 X = 3-benzyloxy; R³ =CH(CH₃)₂ 87% 148 X = 4-benzyloxy; R³ = CH(CH₃)₂ 72% 149 X = 4-CH₃; R³ =2-(benzyloxy)-5-chloro-phenyl 75% A = (CH₃—S)C(CH₃)₂ 150 X = 3-CF₃; R³ =2-(benzyloxy)phenyl 70% 151 X = 4-benzyloxy; R³ = 2-(benzyloxy)phenyl56% 152 X = 4-F; R³ = 2-(benzyloxy)phenyl 63% 153 X = 3-F; R³ =2-(benzyloxy)phenyl 70% 154 X = 3-Cl; R³ = 2-(benzyloxy)phenyl 46% 155 X= 3-Br; R³ = 2-(benzyloxy)phenyl 28% 156 X = 3-F; 4-F; R³ =2-(benzyloxy)phenyl 61% 157 X = 4-ethyl; R³ = 2-(benzyloxy)phenyl 83%158 X = 3-ethyl; R³ = 2-(benzyloxy)phenyl 76% 159 X = 3-methyl;4-methoxy; R³ = 2-(benzyloxy)phenyl 93% 160 X = 3-benzyloxy; R³ =2-methylphenyl 12% 161 X = 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy];88% R³ = HC(CH₃)₂ 162 X = 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]; 36%R³ = 2-chlorophenyl 163 X = 4-{[tert-butyl(dimethyl)silyl]oxy}; R³ =2-fluorophenyl 48% 164 X = 3-CH₃, 5-CH₃; R³ = 2-(benzyloxy)phenyl 72%165 X = 3-CH₃; R³ = 2-(benzyloxy)-5-chlorophenyl 72% 166 X = 4-CH₃; R³ =2-(benzyloxy)-5-chlorophenyl 60% ^(a)Crude compounds were purifiedfurther by trituration with diethyl ether.

Preparations 124, 132 and 133: crude compounds were purified by columnchromatography on silica gel, eluting with dichloromethane: 7Mmethanolic ammonia, 100:0 to 97.5:2.5. This was followed by furtherpurification using reversed phase column chromatography on C18 silicagel, eluting with water/7M methanolic ammonia (98:2):acetonitrile/7Mmethanolic ammonia (98:2), 75:25 to 25:75.

Preparation 134: crude compound was purified by column chromatography onsilica gel, eluting with dichloromethane: 7M methanolicammonia/dichloromethane (10:90), 100:0 to 50:50. This was followed byfurther purification by trituration withdichloromethane:methanol:diethyl ether.

Preparation 160: prepared from the products of preparations 17 and 206

Preparation 163: prepared from the products of preparations 104 and 214

Preparation 165 and 166: were prepared from the appropriateaminopyrazoles and the product of preparation 208. The crude compoundswere purified by column chromatography on silica gel, eluting withhexane:ethyl acetate, 90:10, followed by pentane:ethyl acetate, 80:20 to20:80, followed by ethyl acetate:methanol, 100:0 to 50:50.

Preparation 167N-[2-({3-2-(benzyloxy)phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-(3-tert-butyl-1-pyridin-3-yl-1H-pyrazol-5-yl)urea

The title compound was prepared from the product of preparations 46 and90, using the same method as that described for preparation 121, in 15%yield.

Preparation 168N-[2-({3-2-(benzyloxy)phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-(3-tert-butyl-1-pyridin-2-yl-1H-pyrazol-5-yl)urea

The title compound was prepared from the product of preparations 46 and91, using the same method as that described for preparation 121, in 63%yield.

Preparation 169N-[2-({3-2-(benzyloxy)phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-(3-[1,1-dimethyl-2-(methylthio)ethyl]-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)urea

Pyridine (64 μL, 0.8 mmol) and phenylchloroformate (110 mg, 0.70 mmol)were added sequentially to an ice-cooled solution of the product ofpreparation 113 (250 mg, 0.62 mmol) in tetrahydrofuran (10 mL) and themixture was stirred at 0° C. for 10 minutes and at room temperature for40 minutes. The reaction mixture was then diluted with ethyl acetate,washed with water, dried over magnesium sulfate and concentrated invacuo. The residue was dissolved in dimethylsulfoxide (5 mL), theproduct of preparation 46 (332 mg, 0.70 mmol) andN,N-ethyldiisopropylamine (0.17 mL, 1 mmol) were added and the mixturewas stirred at 50° C. for 90 minutes, The reaction mixture was thencooled to room temperature, diluted with water and washed with 0.1Mcitric acid, saturated sodium hydrogen carbonate solution. The organicsolution was dried over magnesium sulfate and concentrated in vacuo toafford the title compound as a yellow foam in quantitative yield, 614mg.

Preparation 170N-[2-({3-2-(benzyloxy)phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-(3-(1,1-dimethylpropyl)-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)urea

The title compound was prepared from the products of preparations 114and 46, using the same method as that described for preparation 169. Thecrude compound was purified by column chromatography on silica gel,eluting with dichloromethane:ethyl acetate, 100:0 to 30:70, to affordthe desired product as a white foam in 59% yield.

Preparation 171N-{1-[3-(Benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 63 and206, using the same method as that described for preparation 169. Thecrude compound was purified by column chromatography using a 12 g ISCOsilica cartridge, eluting with ethyl acetate, to afford the desiredproduct in 43% yield.

Preparation 172N-(2-{[3-(2-Hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea

The title compound was prepared from the products of preparations 85 and109, using the same method as that described for preparation 169. Thecrude compound was purified by column chromatography on silica gel,eluting with dichloromethane:methanol, 95:5, to afford the desiredproduct in 33% yield.

Preparation 173N-{2-[(3-Isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-N′-(3-[1-(methylthio)ethyl]-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)urea

A mixture of the product of example 26 (89 mg, 0.15 mmol),2-(2-bromoethoxy)tetrahydro-2H-pyran (36 mg, 0.17 mmol) and potassiumcarbonate (28 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) was stirredat room temperature for 18 hours and heated at 60° C. for 12 hours. Thereaction mixture was then cooled to room temperature diluted with ethylacetate and washed with water and brine. The organic solution was thendried over magnesium sulfate concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol:0.88 ammonia, 100:0:0 to 94:6:1, to afford thetitle compound as a glass in 67% yield.

Preparation 174N-{1-[3-(Benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-[(3-{2-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

The title compound was prepared from the product of preparation 123 and2-<2-bromoethoxy)tetrahydro-2H-pyran, using the same method as thatdescribed for preparation 111, as a white foam in 75% yield.

Preparation 175N-(3-tert-Butyl-1-{4-[2-tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 257 and2-(2-bromoethoxy)tetrahydro-2H-pyran, using the same method as thatdescribed for preparation 111, as a pale yellow foam in 45% yield.

Preparation 176 [5-(Benzyloxy)-2-chlorophenyl]methanol

The title compound was prepared from the product of preparation 49,using the same method as that described for preparation 26. The crudecompound was triturated with diethyl ether to afford the desired productas a white solid in 91% yield.

Preparation 177 5-(Benzyloxy)-2-chlorobenzaldehyde

The title compound was prepared from the product of preparation 176,using a similar method as that described for preparation 27. The crudecompound was re-crystallised from isopropyl ether to afford the desiredproduct as a solid in 67% yield.

Preparations 178 to 183

The following compounds, of the general formula shown below wereprepared by a method similar to that described for preparation 30, usingthe product of preparation 25 and the appropriate commercially availablealdehyde. For preparation 182, the starting material4-benzyloxy-2-chloro benzaldehyde was prepared as described in J. Chem.Soc. Perkin Trans 1990, (2), 253.

No. Data Yield 178 Z = 2-ethyl 84% 179 Z = 2-methyl Quant 180 Z =2-(methylthio) 89% 181 Z = 2-chloro 98% 182 Z = 2-chloro, 4-benzyloxy89% 183 Z = 2-benzyloxy, 5-chloro 94%

Preparation 184 6-Bromo-3-(2-ethylphenyl)[1,2,4]triazolo[4,3-a]pyridine

(Diacetoxyiodo)benzene (6.95 g, 22 mmol) was added to a solution of theproduct of preparation 178 (5.46 g, 18 mmol) in dichloromethane (200 mL)and the mixture was stirred at room temperature for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting with ethylacetate:dichloromethane, 50:50, to afford the title compound as a solidin quantitative yield.

Preparation 185 6-Bromo-3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 181,using the same method as that described for preparation 184. The crudecompound was further purified by trituration with ethyl acetate toafford the desired product in 73% yield.

Preparation 1866-Bromo-3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridine

(Diacetoxyiodo)benzene (500 mg, 1.55 mmol) was added to an ice-cooledsolution of the product of preparation 180 (500 mg, 1.55 mmol) and themixture was stirred for 6 hours, allowing the temperature to rise to 25°C. Further (diacetoxyiodo)benzene (500 mg, 1.55 mmol) was added andstirring continued for 18 hours at room temperature. The reactionmixture was then concentrated in vacuo and the residue was purified bycolumn chromatography on silica gel, eluting with ethyl acetate toafford the title compound as a white solid in 68% yield.

Preparation 187 6-Bromo-3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridine

Ammonium eerie nitrate (35 g, 63.76 mmol) was added to a solution of theproduct of preparation 179 (9.25 g, 31.88 mmol) in ethanol (190 mL) anddichloromethane (60 mL) and the mixture was stirred for 72 hours at roomtemperature. The reaction mixture was then concentrated in vacuo and theresidue was partitioned between ethyl acetate (200 mL) and water (100mL). The organic solution was separated, washed with water (4×100 mL),dried over sodium sulfate and concentrated in vacuo. Purification of theresidue by column chromatography on silica gel, eluting withpentane:ethyl acetate, 75:25, followed by dichloromethane:ethanol,50:50, afforded the title compound in 21% yield, 1.94 g.

Preparation 188 6-Bromo-3-(2-fluorophenyl)[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from 2-fluorobenzaldehyde and theproduct of preparation 25, using the same method as that described forpreparation 32, as a white powder in 54% yield.

Preparation 1896-Bromo-3-(2-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridine

A mixture of 2-methoxybenzaldehyde (10 g, 73.4 mmol) and the product ofpreparation 25 (13.8 g, 73.4 mmol) in dichloromethane (10 mL) andethanol (100 mL) was heated to 65° C. for 5 minutes. The mixture wasthen cooled to room temperature and filtered off. The residue wasre-dissolved in dichloromethane (50 mL) and ethanol (50 mL), iodobenzenediacetate (23.66 g, 73.4 mmol) was added and the reaction mixture wasthen stirred at room temperature for 90 minutes. The mixture wasconcentrated in vacuo and the residue was triturated three times withdiethyl ether to afford the title compound as a white solid in 64%yield, 14.2 g.

Preparation 1906-Bromo-3-(2-chloro-3-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridine

A mixture of 2-chloro-3-methoxybenzaldehyde [(10 g, 58.6 mmol), WO2005/007165, p47] and the product of preparation 25 (11.13 g, 58.6 mmol)in ethanol (70 mL) was heated to 70° C. for 2.5 hours. Iodobenzenediacetate (24.5 g, 76 mmol) was added and the reaction mixture wasdiluted with ethanol (40 mL) and stirred at room temperature for 18hours. The resulting precipitate was filtered off, washing through withethanol, and dried under vacuum to afford the title compound as a solidin 64% yield, 12.70 g

Preparation 1913-[5-(Benzyloxy)-2-chlorophenyl]-6-bromo[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 177,using a similar method to that described for preparation 190, as a solidin 60% yield.

Preparation 1923-[4-(Benzyloxy)-2-chlorophenyl]-6-bromo[1,2,4]triazolo[4,3-a]pyridine

A mixture of the product of preparation 182 (53.4 g, 128 mmol) andiodobenzene diacetate (41.3 g, 128 mmol) in dichloromethane (50 mL) andethyl acetate (50 ml) was stirred at room temperature for 18 hours. Theresulting yellow precipitate was filtered off, affording a first portionof title compound. The filtrate was then treated with dichloromethane(50 mL) and diethyl ether (100 mL) and the resulting yellow precipitatewas filtered off to afford further title compound, providing a totalyield 37.1 g (70%).

Preparation 1933-[2-(Benzyloxy)-5-chlorophenyl]-6-bromo[1,2,4]triazolo[4,3-a]pyridine

A suspension of the product of preparation 183 (6.2 g, 14.8 mmol) indichloromethane (300 mL) and ethanol (100 mL) was warmed to 40° C.Iodobenzene diacetate (6.39 g, 19.24 mmol) was added and the mixture wasstirred at 40° C. for 10 minutes then allowed to cool to roomtemperature over 3 hours. The reaction mixture was diluted withdichloromethane (400 mL), washed with 5% sodium bisulphite solution (300mL) and water (300 mL), dried over magnesium sulfate and concentrated invacuo. The residue was then triturated with diethyl ether to afford thetitle compound as a white solid in 92% yield, 5.7 g.

Preparations 194 to 203

The following compounds, of the general formula shown below wereprepared by a method similar to that described for preparation 35, usingthe appropriate starting material and 2-mercaptobenzyl alcohol.

No. Data Yield 194 R³ = 2-ethylphenyl 75% 195 R³ = 2-methylphenyl 77%196 R³ = 2-(methylthio)phenyl 48% 197 R³ = 2-fluorophenyl 67% 198 R³ =2-methoxyphenyl 61% 199 R³ = 2-chlorophenyl 93% 200 R³ =2-chloro-3-methoxyphenyl 91% 201 R³ = 2-chloro-4-benzyloxyphenyl 87% 202R³ = 2-chloro-5-benzyloxyphenyl 71% 203 R³ = 2-benzyloxy-5-chlorophenyl37%

Preparation 195: The crude compound was purified by columnchromatography on silica gel, eluting with ethylacetate:dichloromethane, 50:50, followed by dichloromethane:methanol,95:5.

Preparation 196: The crude compound was purified by columnchromatography on silica gel, eluting with dichloromethane:ethylacetate, 40:60 to 0:100.

Preparation 197, 198 and 202: Crude compounds were triturated withdiethyl ether

Preparation 204(2-{[3-(2-Ethylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)aminehydrochloride

Methanesulfonic anhydride (5 g, 29 mmol) was added to a solution of theproduct of preparation 194 (3.5 g, 9.7 mmol) andN,N-ethyldiisopropylamine (6.8 mL, 38.8 mmol) in dichloromethane (100mL) and the mixture was stirred at room temperature for 90 minutes. 7MMethanolic ammonia (140 mL) was then added and the mixture was stirredat room temperature for 72 hours. The reaction mixture was thenconcentrated in vacuo and the residue was dissolved in dichloromethane(200 mL) and washed with sodium hydrogen carbonate solution (2×200 mL)and 2M hydrochloric acid (4×50 mL). The acidic washings were combined,basified with 2M sodium hydroxide to pH8 and extracted withdichloromethane (3×100 mL). The combined organic solution was dried oversodium sulfate, concentrated in vacuo and the residue was re-dissolvedin dichloromethane. The resulting solution was cooled in an ice bath andhydrogen chloride gas was then bubbled through until saturationoccurred. The reaction mixture was then concentrated in vacuo and theresidue was azeotroped with diethyl ether, followed by dichloromethaneto afford the title compound as an orange foam in 43% yield, 1.66 g.

Preparation 205(2-{[3-(2-Chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)aminehydrochloride

Methanesulfonic anhydride (4.99 g, 28.66 mmol) was added to an ice-coldsolution of the product of preparation 199 (5.27 g, 14.33 mmol) andN,N-ethyldiisopropylamine (7.4 mL, 42.99 mmol) in dichloromethane (150mL) and the mixture was stirred at 0° C. for 10 minutes and at roomtemperature for 4 hours. 7M Methanolic ammonia (143 mL) was then addedand the mixture was stirred at room temperature for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue wasdissolved in dichloromethane (150 mL) and washed with sodium hydrogencarbonate solution (150 mL) and 2M hydrochloric acid (3×70 mL). Theacidic washings were combined, basified with 2M sodium hydroxide (250mL) and extracted with dichloromethane (4×125 mL). The combined organicsolution was dried over magnesium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol:0.88 ammonia, 95:5:0.5, to give an orangefoam. This foam was then dissolved in dichloromethane (15 mL) andacidified with hydrochloric acid (4M in dioxane, 3.1 mL). The mixturewas azeotroped with methanol and dichloromethane, and the residue wastriturated with diethyl ether to afford the title compound as a whitesolid in 48% yield, 2.82 g

Preparation 206(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)amine

Methanesulfonic anhydride (2.7 g, 15.49 mmol) was added to a solution ofthe product of preparation 195 (1.8 g, 5.18 mmol) andN,N-ethyldiisopropylamine (3.6 mL, 20.72 mmol) in dichloromethane (50mL) and the mixture was stirred at room temperature for 1 hour. 7MMethanolic ammonia (140 mL) was then added and the mixture was stirredat room temperature for 72 hours. The reaction mixture was then washedwith sodium hydrogen carbonate solution, brine and 2M hydrochloric acid(3×100 mL). The acidic washings were combined, basified with 2M sodiumhydroxide to pH8 and extracted with dichloromethane (5×150 mL). Thecombined organic solution was dried over sodium sulfate and concentratedin vacuo to afford the title compound as an orange gum in 55% yield, 982mg.

Preparation 207[2-({3-[2-(Methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]amine

The title compound was prepared from the product of preparation 196,using the same method as that described for preparation 206, as a paleorange foam in 49% yield.

Preparation 208[2-({3-[2-(Benzyloxy)-5-chlorophenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]amine

The title compound was prepared from the product of preparation 203,using the same method as that described for preparation 206. The crudecompound was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol:0.88 ammonia, 97.3:0.2 to 95:5:0.5, toafford the desired compound as a pale brown gum in 52% yield.

Preparation 2096-{[2-(Azidomethyl)phenyl]thio}-3-(2-fluorophenyl)[1.2.4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 197 anddiphenylphosphoryl azide, using a method similar to that of preparation39, in 95% yield.

Preparation 2106-{[2-(Azidomethyl)phenyl]thio}-3-(2-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 198 anddiphenylphosphoryl azide, using a method similar to that of preparation39, in 86% yield.

Preparation 2116-{[2-(azidomethyl)phenyl]thio}3-(2-chloro-3-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 200 anddiphenylphosphoryl azide, using a method similar to that of preparation39. The crude compound was triturated with dichloromethane/diethyl etherto afford the desired product in 59% yield.

Preparation 2126-{[2-(Azidomethyl)phenyl]thio}-3-[4-(benzyloxy)-2-chlorophenyl][1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 201 anddiphenylphosphoryl azide, using a method similar to that of preparation39, as a brown foam in quantitative yield.

Preparation 2136-{[2-(Azidomethyl)phenyl]thio}-3-[5-(benzyloxy)-2-chlorophenyl][1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 202 anddiphenylphosphoryl azide, using a method similar to that of preparation39, in quantitative yield.

Preparation 214(2-{[3-(2-Fluorophenyl)[1,2,4]triazolo[4,3-a]Pyridin-6-yl]thio}benzyl)aminehydrochloride

Triphenylphosphine (8.53 g, 32.5 mmol) and water (0.58 mL, 32.5 mmol)were added to a solution of the product of preparation 209 (10.2 g, 27.1mmol) in tetrahydrofuran (100 mL) and the mixture was stirred at roomtemperature for 18 hours. The reaction mixture was then concentrated invacuo and the residue was dissolved in dichloromethane (200 mL).Hydrochloric acid (4M in dioxane, 8 mL) was added dropwise and themixture was stirred for 72 hours at room temperature. The resultingprecipitate was filtered off and triturated with dichloromethane toafford the title compound as a solid in 35% yield, 3.7 g.

Preparation 215(2-{[3-(2-Methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)aminehydrochloride

The title compound was prepared from the product of preparation 210,using the same method as that described for preparation 214, as a solidin 52% yield.

Preparation 216(2-{[3-(2-Chloro-3-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)aminehydrochloride

The title compound was prepared from the product of preparation 211,using the same method as that described for preparation 214, as a solidin 72% yield.

Preparation 217[2-({3-[4-(benzyloxy)-2-chlorophenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-aminehydrochloride

The title compound was prepared from the product of preparation 212,using a similar method to that described for preparation 214, as a solidin 64% yield.

Preparation 218[2-({3-[5-(Benzyloxy)-2-chlorophenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]amine

The title compound was prepared from the product of preparation 213,using a similar method to that described for preparation 214, as a solidin 85% yield.

Preparation 219N-(3-tert-Butyl-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-(2-{[3-(2-fluorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

A mixture of the product of preparation 214 (360 mg, 0.93 mmol), theproduct of preparation 116 (446 mg, 0.93 mmol) andN,N-ethyldiisopropylamine (0.39 mL, 2.23 mmol) in dimethylsulfoxide (4mL) was stirred at room temperature for 72 hours and at 60° C. for 1hour. The reaction mixture was then cooled to room temperature, dilutedwith ethyl acetate (50 mL) and washed with 0.5M hydrochloric acid,saturated sodium hydrogen carbonate solution and brine. The organicsolution was dried over sodium sulfate concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 99:1 to 93:7, to afford the titlecompound as a light brown oil in 33% yield, 223 mg.

Preparation 220N-(3-tert-Butyl-1-{3-[2-tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 205and 116, using the same method as that described for preparation 219, asa white foam in 45% yield.

Preparation 221N-(3-tert-butyl-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-(2-{[3-(2-isopropylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparation 237 and116, using the same method as that described for preparation 219, as awhite foam in 37% yield.

Preparation 222N-(3-tert-Butyl-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-(2-{[3-(2-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 215and 116, using the same method as that described for preparation 219, asa white foam in 46% yield.

Preparation 223N-{1-[3-(Benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 118and 205, using the same method as that described for preparation 219, asa pale yellow foam in 59% yield.

Preparation 224N-{1-[3-(Benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[2-({3-2-(benzyloxy)phenyl[1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

The title compound was prepared from the products of preparations 118and 46, using the same method as that described for preparation 219, asa white solid in 58% yield.

Preparation 225N-{1-(3-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

The title compound was prepared from the products of preparations 120and 43, using the same method as that described for preparation 219, asa white foam in 69% yield.

Preparation 226N-{1-(3-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-fluorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 120and 214, using the same method as that described for preparation 219, asan off-white foam in 48% yield.

Preparation 227N-{1-(3-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 120and 215, using the same method as that described for preparation 219, asa white foam in 53% yield.

Preparation 228N-{1-[3-(Benzyloxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-ethylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 204 andpreparation 17, using the same method as that described for preparation121, in 41% yield.

Preparation 229N-{1-[3-(Benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

The title compound was prepared from the product of preparation 207 and63, using the same method as that described for preparation 121, as awhite solid in 52% yield.

Preparation 230N-{1-[4-(Benzyloxy)phenyl]-3-[1-methyl-1-(methylphenyl)ethyl]1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 92 and206, using the same method as that described for preparation 121, in 19%yield.

Preparation 231N-[2-({3-[4-(Benzyloxy)-2-chlorophenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-[3-tert-butyl-1-(3,4-difluorophenyl)-1H-pyrazol-5-yl]urea

The title compound was prepared from the products of preparations 95 and217, using the same method as that described for preparation 121, as abrown powder in 59% yield.

Preparation 232N-[2-({3-[5-(Benzyloxy)-2-chlorophenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-[3-tert-butyl-1-(3,4-difluorophenyl)-1H-pyrazol-5-yl]urea

The title compound was prepared from the products of preparations 218and 95, using the same method as that described for preparation 121, asa white powder in 40% yield.

Preparation 2346-Bromo-3-(2-isopropylphenyl)[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 25 and2-isopropylbenzaldehyde, using the same method as that described forpreparation 189. The crude compound was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol,95:5, to afford the desired product as a yellow liquid in 35% yield.

Preparation 235[3-(2-isopropylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]-methanol

The title compound was prepared from the product of preparation 234 and2-mercaptobenzyl alcohol, using the same method as that described forpreparation 35. The crude compound was purified by columnchromatography, eluting with dichloromethane:methanol, 95:5, to affordthe desired product as a dark brown oil in 45% yield.

Preparation 2366-{[2-(Azidomethyl)phenyl]thio}-3-(2-isopropylphenyl)[1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared from the product of preparation 235 anddiphenylphosphoryl azide, using the same method as that described forpreparation 39, as a brown oil in 66% yield.

Preparation 237(2-{[3-(2-Isopropylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)aminehydrochloride

The title compound was prepared from the product of preparation 236,using the same method as that described for preparation 214, as a whitesolid in 805 yield.

Preparation 238N-(2-{[3-(2-Fluorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-(3-[1-methyl-1-(methylthio)ethyl]-1-(3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]-phenyl)-1H-pyrazol-5-yl)urea

A mixture of the product of preparation 117 (399 mg, 0.78 mmol), theproduct of preparation 214 (307 mg, 0.78 mmol) andN,N-ethyldiisopropylamine (0.30 mL, 1.70 mmol) in dimethylsulfoxide (2mL) was stirred at room temperature for 18 hours. The reaction mixturewas then diluted with ethyl acetate (50 mL) and washed with 0.5Mhydrochloric acid, saturated sodium hydrogen carbonate solution andbrine. The organic solution was dried over sodium sulfate concentratedin vacuo and the residue was purified by column chromatography on silicagel, eluting with dichloromethane:methanol, 100:0 to 95:5, to afford thetitle compound as a white foam in 40% yield, 266 mg.

Preparation 239N-(2-{[3-(2-Methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-(3-[1-methyl-1-(methylthio)ethyl]-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)urea

The title compound was prepared from the products of preparations 117and 215, using the same method as that described for the product ofpreparation 238, as a white foam in 45% yield.

Preparation 2401-[3-(Benzyloxy)phenyl]-3-(1,1-dimethylpropyl)-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 47 and3-benzyloxyphenylhydrazine hydrochloride, using the same method as thatdescribed for preparation 7. The crude compound was triturated withdiethyl ether to afford the desired product as a pink solid in 91%yield.

Preparation 241 3-[5-Amino-3-(1,1-dimethylpropyl)-1H-pyrazol-1-yl]phenol

The title compound was prepared from the product of preparation 240,using the same method as that described for example 99, as a yellow foamin 49% yield.

Preparation 2421-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 241 andtert-butyldimethylsilyl chloride, using the same method as thatdescribed for preparation 99, as a solid in 69% yield.

Preparation 243N-[1-(3-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

The title compound was prepared from the products of preparations 242and 207, using the same method as that described for preparation 169, in47% yield.

Preparation 244 1-[4-(Benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-amine

The title compound was prepared from 4,4-dimethyl-3-oxopentane nitrileand 4-benzyloxyphenylhydrazine hydrochloride, using the same method asthat described for preparation 7, as a pale pink powder in quantitativeyield.

Preparation 245 4-(5-Amino-3-tert-butyl-1H-pyrazol-1-yl)phenol

The title compound was prepared from the product of preparation 244,using the same method as that described for example 99, as a brownpowder in 72% yield.

Preparation 2463-tert-Butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-amine

The title compound was prepared from the product of preparation 245 andtert-butyldimethylsilyl chloride, using the same method as thatdescribed for preparation 99, as a white solid in 18% yield.

Preparation 247Phenyl[3-tert-butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-yl]carbamate

The title compound was prepared from the product of preparation 246 andphenylchloroformate, using the same method as described for preparation116 in quantitative yield.

Preparation 248N-[3-tert-Butyl-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-fluorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 214and 247, using the same method as that described for preparation 219, asa colourless glass in 93% yield.

Preparation 249 4-(Methylthio)benzaldehyde(5-bromopyridin-2-yl)hydrazone

The title compound was prepared from the product of preparation 25 and4-(methylthio)benzaldehyde, using the same method as that described forpreparation 30, as a pale yellow solid in 92% yield.

Preparation 2506-Bromo-3-[4-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridine

The title compound was prepared form the product of preparation 249,using the same method as described for preparation 184, as a white solidin 72% yield.

Preparation 251[2-({3-[4-(Methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)phenyl]methanol

The title compound was prepared from the product of preparation 250 and2-mercaptobenzyl alcohol, using the same method as that described forpreparation 35, as a white solid in 58% yield.

Preparation 252[2-({3-[4-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]aminehydrobromide

Thionyl bromide (235 μL, 3.03 mmol) was added to an ice-cooled solutionof the product of preparation 251 (384 mg, 1.01 mmol) in dichloromethane(10 mL) and the mixture was stirred for 1 hour. The reaction mixture wasthen concentrated in vacuo and the residue was re-dissolved indichloromethane. The solution was cooled to 0° C., 7M methanolic ammonia(15 mL) was added dropwise and the mixture was stirred for 18 hours atroom temperature. The reaction mixture was then concentrated in vacuoand the residue was diluted with dichloromethane, washed with saturatedsodium hydrogen carbonate solution, dried over magnesium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography on silica get, eluting with methanol:ethyl acetate, 20:80to 50:50, then afforded the title compound as a pale yellow solid in 40%yield, 154 mg.

Preparation 253N-{1-[3-(benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[2-({3-[4-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

The title compound was prepared from the products of preparations 252and 63, using the same method as that described for the product ofpreparation 121, as a white solid in 65% yield.

Preparation 254N-[2-({3-[2-(Benzyloxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-[3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl]urea

The title compound was prepared from the products of preparations 62 and46, using the same method as that described for preparation 121. Thecrude compound was triturated with diethyl ether to afford the desiredproduct as a solid in 85% yield.

Preparation 255N-(2-{[3-(2-isopropylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-(3-[1-methyl-1-(methylthio)ethyl]-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]phenyl}-1H-pyrazol-5-yl)urea

The title compound was prepared from the products of preparation 237 and117, using the same method as that described for preparation 219, as awhite foam in 48% yield.

Preparation 256N-{1-[4-(Benzyloxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]-thio}benzyl)urea

The title compound was prepared from the product of preparations 103 and205, using the same method as that described for preparation 219, as afoam in 74% yield.

Preparation 257N-[3-tert-Butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chlorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 256,using the same method as that described for preparation 101. The crudecompound was further purified by triturated with diethyl ether to affordthe title compound the title compound as a white solid in 47% yield.

Example 1N-{3-tert-Butyl-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

The product of preparation 7 (0.13 g, 0.50 mmol) was added to a solutionof N,N′-carbonyldiimidazole (0.49 g, 3.00 mmol) in dichloromethane (10mL) and the mixture was stirred at room temperature for 20 hours. Thereaction mixture was then diluted with brine and stirred vigorously for15 minutes. The aqueous layer was separated and extracted withdichloromethane (3×15 mL) and the combined organics were dried oversodium sulfate and concentrated in vacuo. The product of preparation 43(0.15 g, 0.49 mmol) was added to a solution of the residue andN-ethyldiisopropylamine (65 mg, 0.50 mmol) in 1,4-dioxane (10 mL) andthe mixture was stirred for 18 hours at room temperature. The reactionmixture was then diluted with ethyl acetate, washed with water (25 mL)and brine (25 mL), dried over sodium sulphate and concentrated in vacuo.The residue was purified by column chromatography on silica gel, elutingwith dichloromethane:7M ammonia in methanol, 100:0 to 97.5:2.5. Theappropriate fractions were concentrated in vacuo and the residue wasre-purified twice using a Flashmaster® silica column, eluting withdichloromethane: 7M ammonia in methanol, 100:0 to 97.5:2.5 to afford thetitle compound.

¹H NMR (300 MHz, CDCl₃) δ: 1.20 (d, 6H), 1.40 (s, 9H), 2.29 (s, 3H),3.15 (m, 1H), 4.50 (d, 2H), 6.30 (s, 1H), 6.72 (d, 1H), 6.80 (d, 2H),7.05 (d, 2H), 7.21 (m, 5H), 7.48 (d, 1H), 7.65 (S, 1H), 8.15 (s, 1H)LRMS: m/z API-ES 586.7 [MH]⁺

Examples 2 to 12

The following compounds, of the general formula shown before wereprepared by a method similar to that described for example 1, using theproduct of preparation 43, N,N′-carbonyldiimidazole and the appropriatepyrazole starting material. The reactions were monitored by tlc analysisand were stirred at room temperature for 20-48 hours.

No. X Y Data Yield  2 SCH₃ H ¹H NMR (300 MHz, CDCl₃) δ: 55% 1.30(m, 15H), 2.25(s, 3 H), 3.15(m, 1 H), 4.55(d, 2 H), 6.32(s, 1 H), 6.75-7.30(m,8 H), 7.45(d, 1 H), 7.72(s, 1 H), 8.40 (brs, 1 H) LRMS: m/z API-ES 586.7[MH]⁺  3 Cl Cl ¹H NMR (400 MHz, CDCl₃) δ: 27% 1.28(m, 15 H), 3.14(m, 1H), 4.55(d, 2 H), 6.33(s, 1 H), 6.87(d, 1 H), 6.99(d, 1 H), 7.09(d, 1H), 7.23(m, 1 H), 7.28(m, 3 H), 7.40 (m, 1 H), 7.45(d, 1 H), 7.54(s, 1H), 7.68(s, 1 H), 8.79(bs, 1 H), LRMS: m/z APCI 608 [MH]⁺  4 H CO₂CH₂CH₃¹H NMR (400 MHz, CDCl₃) δ: 46% 1.24-1.33(m, 18 H), 3.14(m, 1 H), 4.26(q,2 H), 4.54(d, 2 H), 6.33(s, 1 H), 6.85(d, 1 H), 7.03(d, 1 H), 7.19(m, 1H), 7.26(m, 3 H), 7.43(d, 1 H), 7.49(d, 2 H), 7.71 (m, 3 H), 8.56(s, 1H) LRMS: m/z APCI 612 [MH]⁺ Microanalysis: C₃₃H₃₇N₇O₃S. 0.1DCM requires(%): C 64.10; H 6.05; N 15.81; found (%) C 63.85; H 6.14, N 15.43.  5CO₂CH₂CH₃ H ¹H NMR (400 MHz, CDCl₃) δ: 24% 1.28(m, 18 H), 3.15(m, 1 H),4.21(q, 2 H), 4.52(d, 2 H), 6.33(s, 1 H), 6.86(d, 1 H), 7.03(bs, 1 H),7.12(d, 1 H), 7.16-7.27(m, 4 H), 7.40(d, 1 H), 7.59(d, 1 H), 7.66 (d, 1H), 7.71(s, 1 H), 8.08(s, 1 H), 8.31(s, 1 H), LRMS: m/z APCI 612 [MH]⁺ 6 H CN ¹H NMR (400 MHz, CDCl₃) δ: 52% 1.29(m, 15 H), 3.17(m, 1 H),4.55(d, 2 H), 6.30(s, 1 H), 6.94(d, 1 H), 7.13(d, 1 H), 7.24-7.33(m, 4H), 7.40(m, 2 H), 7.45(d, 1 H), 7.65(d, 2 H), 7.74(s, 1 H), 8.64(s, 1H): LRMS: m/z APCI 565 [MH]⁺  7 CN H ¹H NMR (400 MHz, CD₃OD) δ: 58%1.31(s, 9 H), 1.41(d, 6 H), 3.46 (m, 1 H), 4.50(d, 2 H), 6.27(s, 1 H),7.20(d, 1 H), 7.25-7.39(m, 4 H), 7.58-7.64(m, 2 H), 7.71(d, 1 H),7.81(d, 1 H), 7.87(s, 1 H), 8.31(s, 1 H), LRMS: m/z APCI 565 [MH]⁺  8 HH ¹H NMR (300 MHz, DMSO-d₆) Quan- δ: 1.21(s, 9 H), 1.35(d, 6 H), 3.55tita- (m, 1 H), 4.40(d, 2 H), 6.25(s, 1 tive H), 7.10(d, 1 H),7.20-7.30(m, 4 H), 7.35(m, 1 H), 7.50(m, 4 H), 7.65(s, 1 H), 7.70(d, 1H), 8.30(s, 1 H), 8.60(s, 1 H), LRMS: m/z API-ES 540.8 [MH]⁺  9 H CH₃ ¹HNMR (300 MHz, DMSO-d₆) 71% δ: 1.25(s, 9 H), 1.40(d, 6 H), 2.27 (s, 3 H),3.55(m, 1 H), 4.40(d, 2 H), 6.20(s, 1 H), 7.00(m, 1 H), 7.10(d, 1 H),7.20-7.40(m, 8 H), 7.65(d, 1 H), 8.20(s, 1 H), 8.56(s, 1 H), LRMS: m/zAPI-ES 554.8 [MH]⁺ 10 H O—CH₃ ¹H NMR (300 MHz, CDCl₃) δ: 80% 1.30(s, 9H), 1.36(d, 6 H), 3.16 (m, 1 H), 3.68(s, 3 H), 4.54(d, 2 H), 6.27(s, 1H), 6.42(m, 1 H), 6.66(d, 2 H), 6.85(d, 1 H), 7.17- 7.31(m, 7 H),7.38(d, 1 H), 7.70(s, 1 H), LRMS: m/z API-ES 570.8 [MH]⁺ 11 CH₃ O—CH₃ ¹HNMR (300 MHz, CDCl₃) δ: 49% 1.30(s, 9 H), 1.38(d, 6 H), 2.05(s, 3 H),3.20(m, 1 H), 3.71(s, 3 H), 4.60(d, 2 H), 6.27(m, 2 H), 6.60(d, 1 H),6.88(d, 1 H), 7.10 (d, 1 H), 7.16(m, 2 H), 7.20-7.34 (m, 4 H), 7.40(d, 1H), 7.75(s, 1 H), LRMS: m/z API-ES 584.6 [MH]⁺ 12 O—CH₃ H ¹H NMR (300MHz, CDCl₃) δ: 88% 1.30(m, 15 H), 3.15(m, 1 H), 3.62(s, 3 H), 4.55(d, 2H), 6.32(s, 1 H), 6.55(d, 1 H), 6.85-7.10(m, 5 H), 7.20-7.40(m, 5 H),7.72(s, 1 H), 8.40(brs, 1 H), LRMS: m/z API-ES 570.8 [MH]⁺

Example 3: Reaction earned out in dichlorometnane only. Purified usingBiotage® silica column, eluting with ethyl acetate.

Example 4: Reaction carried out in dichloromethane only. Purified byISCO Companion® silica column, eluting with pentane:ethyl acetate,100:0, 50:50, 20:80.

Example 5: Purified by ISCO Companion® silica column, eluting with ethylacetate.

Example 9: Crude product is further purified by re-crystallisation fromdichloromethane/diethyl ether to afford final compound.

Example 11: Crude compound is further purified using a Flashmaster®silica column, eluting with ethyl acetate.

Example 13N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chloro-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparation 21 and45, using a method similar to that of example 1, as a white foam in 54%yield.

¹H NMR (300 MHz, CDCl₃) δ: 1.30 (s, 9H), 2.40 (s, 3H), 4.45 (d, 2H),6.30 (s, 1H), 6.85 (dd, 1H), 7.00 (d, 1H), 7.15 (d, 1H), 7.20-7.32 (m,10H), 7.40 (d, 1H), 7.65 (s, 1H), 7.70 (d, 1H) LRMS: m/z API-ES 638.5[MH]⁺

Example 14N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparation 21 and44, using a method similar to that of example 1, in 51% yield.

¹H NMR (300 MHz, DMSO-d₆) δ: 1.25 (s, 9H), 2.30 (s, 3H), 4.35 (d, 2H),6.20 (s, 1H), 6.95-7.10 (m, 3H), 7.20-7.40 (m, 9H), 7.45 (d, 1H), 7.85(d, 1H), 7.99 (s, 1H), 8.20 (s, 1H) LRMS: m/z API-ES 638.5 [MH]⁺

Example 15N-{3-[1,1-Dimethyl-2-(methylthio)ethyl]-1-phenyl-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

The product of preparation 15 (209 mg, 0.80 mmol) was added to asolution of N,N′-carbonyldiimidazole (810 mg, 5.00 mmol) indichloromethane (10 mL) and the mixture was stirred at room temperaturefor 24 hours. The reaction mixture was then diluted with water andextracted with dichloromethane (3×25 mL). The combined organic solutionwas dried over magnesium sulfate and concentrated in vacuo. The productof preparation 43 (215 mg, 0.64 mmol) was added to a solution of theresidue and N-ethyldiisopropylamine (129 mg, 1 mmol) in dichloromethane(10 mL) and the mixture was stirred for 24 hours at room temperature.The reaction mixture was then diluted with 0.1M hydrochloric acid (25ml) and extracted with dichloromethane (3×25 mL). The combined organicsolution was dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel, elutingwith ethyl acetate:methanol, 100:0 to 85:15. The appropriate fractionswere concentrated in vacuo and the residue was crystallised from ethylacetate to afford the title compound in 55% yield, 206 mg.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.29 (s, 6H), 1.34 (d, 6H), 1.97 (s, 3H),2.77 (s, 2H), 3.55 (m, 1H), 4.40 (d, 2H), 6.29 (s, 1H), 7.02 (t, 1H),7.10 (d, 1H), 7.26 (m, 4H), 7.38 (t, 1H), 7.46 (m, 4H), 7.70 (d, 1H),8.35 (s, 1H), 8.60 (s, 1H) LRMS: m/z APCI 586 [MH]⁺ Microanalysis:C₃₃H₃₅N₇OS₂. 0.2H₂O requires (%): C, 63.17; H, 6.05; N, 16.63. found (%)C, 63.03; H, 6.00; N, 16.42.

Examples 16 to 20

The following compounds, of the general formula shown below wereprepared by a method similar to that described for example 15, using theproduct of preparation 43, N,N′-carbonyldiimidazole and the appropriatepyrazole starting material. The reactions were monitored by tlc analysisand were stirred at room temperature for 0.5-18 hours.

No X Y n Data Yield  6 H CH₃ 1 ¹H NMR (400 MHz, DMSO-d₆) δ: 67% 1.28(s,6 H), 1.34(d, 6 H), 1.96(s, 3 H), 2.34(s, 3 H), 2.76(s, 2 H), 3.55(m, 1H), 4.39(d, 2 H), 6.26(s, 1 H), 7.00(t, 1 H), 7.10(d, 1 H), 7.23-7.33(m,8 H), 7.69(d, 1 H), 8.27(s, 1 H), 8.60(s, 1 H), LRMS: m/z APCI 600 [MH]⁺Microanalysis: C₃₂H₃₇N₇OS₂. requires (%): C 64.08; H 6.22; N 16.35;found (%) C 63.79; H 6.20, N 16.14. 17 H H 0 ¹H NMR (400 MHz, DMSO-d₆)δ: 76% 1.33(d, 6 H), 1.57(s, 6 H), 1.89(s, 3 H), 3.55(m, 1 H), 4.40(d, 2H), 6.36(s, 1 H), 7.06(m, 1 H), 7.10(d, 1 H), 7.26(d, 4 H), 7.40(m, 1H), 7.48(m, 4 H), 7.70(d, 1 H), 8.38(s, 1 H), 8.60(s, 1 H) LRMS: m/zAPCI 572 [MH]⁺ Microanalysis: C₃₀H₃₇N₇OS₂. requires (%): C 63.02; H5.82; N 17.15; found (%) C 62.75; H 5.80, N 17.09. 18 —OCH₂Ph H 0 ¹H NMR(400 MHz, CDCl₃) δ: 1.37(d, 77% 6 H), 1.68(s, 6 H), 1.95(s, 3 H),3.17(m, 1 H), 4.58(d, 2 H), 4.98(s, 2 H), 6.15(bs, 1 H), 6.46(s, 1 H),6.80(d, 1 H), 6.95(d, 1 H), 7.00(d, 1 H), 7.06(bs, 1 H), 7.09(t, 1 H),7.17(t, 1 H), 7.23-7.37(m, 9 H), 7.46(s, 1 H), 7.72(s, 1 H) LRMS: m/zAPCI 678 [MH]⁺ Microanalysis: C₃₃H₃₅N₇OS₂. 0.2 H₂O requires (%): C63.17; H 6.05; N 16.63; found (%) C 63.03; H 6.00, N 16.42. 19 H Cl 0 ¹HNMR (400 MHz, CDCl₃) δ: 1.38(d, 58% 6 H), 1.65(s, 6 H), 1.98(s, 3 H),3.18(m, 1 H), 4.61(d, 2 H), 6.48(s, 1 H), 7.00- 7.65(m, 13 H), m/z ES606 [MH]⁺ C₃₃H₃₂ClN₇OS₂ requires (%): C 59.44; H 5.32; N 16.17; found(%) C 59.29; H 5.19, N 16.07. 20 H CF₃ 0 ¹H NMR (400 MHz, CDCl₃) δ:1.35(d, 87% 6 H), 1.65(s, 6 H), 1.98(s, 3 H), 3.15(m, 1 H), 4.62(d, 2H), 6.49(s, 1 H), 7.20- 7.65(m, 13 H), m/z ES 640 [MH]⁺ C₃₃H₃₂F₃N₇OS₂0.4 H₂O requires (%): C 57.19; H 4.86; N 15.00; found (%) C 57.55; H5.11, N 15.15.

Examples 21 to 23

The following compounds, of the general formula shown below wereprepared by a method similar to that described for example 15, using theproduct of preparation 46 N,N′-carbonyldiimidazole and the appropriatepyrazole starting material. The reactions were monitored by tlc analysisand were stirred at room temperature for 0.5-18 hours.

No X Y Data Yield 21 H H ¹H NMR (400 MHz, CDCl₃) δ: 1.66(d, 6 H), 82%1.34(s, 3 H), 4.51(d, 2 H), 5.02(s, 2 H), 6.20(bs. 1 H), 6.45(s, 1 H),6.86(d, 1 H), 6.99(d, 1 H), 7.05(t, 1 H), 7.10-7.15(m, 5 H),7.17-7.28(m, 7 H), 7.35-7.40(m, 3 H), 7.51- 7.59(m, 2 H), 7.81(s, 1 H),LRMS: m/z APCI 712 [MH]⁺ 22 H Cl ¹H NMR (400 MHz, CDCl₃) δ: 1.65(d, 6H), 75% 1.95(s, 3 H), 4.55(d, 2 H), 5.01(s, 2 H), 6.42(s, 1 H),6.43(brs, 1 H), 6.90(brs, 1 H), 7.05-7.35(m, 15 H), 7.42-7.60(m, 4 H),7.72(brs, 1 H) LRMS: m/z ESI 746 [MH]⁺ 23 H CF₃ ¹H NMR (400 MHz, CDCl₃)δ: 1.65(d, 6 H), 52% 1.95(s, 3 H), 4.55(d, 2 H), 4.97(s, 2 H), 6.49(s, 1H), 6.71(d, 1 H), 6.82(d, 1 H), 6.91(brs, 1 H), 7.00(brs, 1 H),7.01-7.32(m, 10 H), 7.40-7.58(m, 4 H), 7.68(s, 1 H) 8.38(brs, 1 H) LRMS:m/z ESI 780 [MH]⁺

Example 24N-[3-tert-Butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

A solution of the product of example 12 (0.26 g, 0.45 mmol) indichloromethane (5.5 mL) was cooled to 10° C., boron tribromide (1M indichloromethane, 5.5 mL, 5.50 mmol) was added and the mixture wasstirred at room temperature for 18 hours. A solution of ethylenediamine(15% in water, 25 mL) was added dropwise and the mixture was thenacidified with 6M hydrochloric acid to pH1. The aqueous layer wasseparated and extracted with ethyl acetate (3×20 mL) and the combinedorganic solution was dried over sodium sulphate and concentrated invacuo. Purification of the residue by column chromatography on silicagel, eluting with dichloromethane:methanol, 96:4 to 92:8, followed bytrituration with dichloromethane/diethyl ether afforded the titlecompound in 35% yield, 88 mg.

¹H NMR (300 MHz, CDCl₃) δ: 1.20 (s, 9H), 1.40 (d, 6H), 3.60 (m, 1H),4.40 (d, 2H), 6.20 (s, 1H), 6.75 (d, 1H), 6.85 (m, 2H), 7.20 (m, 2H),7.30 (m, 5H), 7.72 (d, 1H), 8.30 (s, 1H), 8.60 (s, 1H), 9.70 (s, 1H)LRMS: m/z API-ES 556.8 [MH]⁺

Example 25N-[3-tert-Butyl-1-(4-hydroxy-3-methylphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

The title compound was prepared from the product of example 11, using amethod similar to example 24. The crude compound was purified using aFlashmaster® silica column, eluting with dichloromethane:7M ammonia inmethanol, 100:0 to 95:5, to afford the desired product in 84% yield.

¹H NMR (300 MHz, DMSO-d₆) δ: 1.20 (s, 9H), 1.35 (d, 6H), 2.14 (s, 3H),3.55 (m, 1H), 4.60 (d, 2H), 6.20 (s, 1H), 6.80 (d, 1H), 6.95-7.05 (m,2H), 7.10 (m, 2H), 7.20-7.34 (m, 4H), 7.70 (d, 1H), 8.10 (s, 1H), 8.60(s, 1H), 9.60 (bs, 1H) LRMS: m/z API-ES 570.6 [MH]⁺

Example 26N-{1-(3-Hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

The title compound was prepared from the product of example 18, using asimilar method to example 24. The crude product was purified by columnchromatography on silica gel, eluting with ethyl acetate:methanol, 100:0to 90:10. The appropriate fractions were concentrated in vacuo and theresidue was re-crystallised from ethyl acetate to afford the titlecompound as a solid in 55% yield.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.34 (d, 6H), 1.57 (s, 6H), 1.88 (s, 3H),3.56 (m, 1H), 4.41 (d, 2H), 6.34 (s, 1H), 6.79 (d, 1H), 6.88 (m, 2H),7.10 (m, 2H), 7.23-7.30 (m, 5H), 7.70 (d, 1H), 8.35 (s, 1H), 8.60 (s,1H), 9.79 (s, 1H) LRMS: m/z APCI 588 [MH]⁺

Examples 27 to 29

The following compounds, of the general formula shown below wereprepared by a method similar to that described for example 24, using theappropriate urea starting material. The reactions were monitored by tlcanalysis and were stirred at room temperature for 0.5-1.0 hours.

No X Y Data 27 H H HRMS: m/z found: 622.2072; C₃₃H₃₂N₇O₂S₂ requires622.2053 28 H Cl HRMS: m/z found: 656.1669; C₃₃H₃₀ClN₇O₂S₂ requires656.1664 29 H CF₃ HRMS: m/z found: 690.1927; C₃₃H₃₀F₃N₇O₂S₂ requires690.1927

Example 303-(3-tert-Butyl-5-{3-[2-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzyl]-ureido}-pyrazol-1-yl)-benzoicacid

A mixture of the product of example 5 (68.5 mg, 0.11 mmol) and 2M sodiumhydroxide solution (1 mL) in dioxan (2 mL) was heated at 90° C. for 18hours. The solvent was then evaporated under reduced pressure and theaqueous residue was diluted with water (10 mL), acidified with 1Mhydrochloric acid to pH3, and extracted with ethyl acetate (2×10 mL).The organic solution was dried over sodium sulfate, concentrated invacuo and the residue was purified by column chromatography on silicagel, eluting with dichloromethane:methanol:acetic acid, 95:5:0.5. Therelevant fractions were concentrated in vacuo and the residue was driedunder vacuum at 50° C. to afford the title compound in 27% yield, 16.8mg.

¹H NMR (400 MHz, CD₃OD) δ: 1.31 (s, 9H), 1.41 (d, 6H), 3.48 (m, 1H),4.49 (s, 2H), 6.28 (s, 1H), 7.19 (d, 1H), 7.23-7.31 (m, 3H), 7.37 (d,1H), 7.52-7.65 (m, 3H), 8.02 (d, 1H), 8.11 (s, 1H), 8.27 (s, 1H) LRMS:m/z APCI 582 [MH]⁺ Microanalysis: C₃₁H₃₃N₇O₃S. 0.55 DCM requires (%): C,60.11; H, 5.45; N, 15.55. found (%) C, 59.76; H, 5.57; N, 15.42.

Example 314-(3-tert-butyl-5-{[({2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzoicacid

A mixture of the product of example 4 (130 mg, 0.21 mmol) and 2M sodiumhydroxide solution (1.5 mL) in dioxan (3 mL) was heated at 90° C. for 16hours. The mixture was then diluted with ethyl acetate (10 mL) andextracted with sodium hydroxide solution (2×5 mL). The aqueous solutionwas acidified to pH5 with 1M hydrochloric acid and extracted with ethylacetate (2×5 mL). The organic solution was dried over sodium sulfate,concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting withdichloromethane:methanol:acetic acid, 95:5:0.5 to 90:10:1. The relevantfractions were concentrated in vacuo, and the residue was azeotropedwith toluene and dried under vacuum at 50° C. to afford the titlecompound in 6% yield, 7 mg.

¹H NMR (400 MHz, CD₃OD) δ: 1.31 (s, 9H), 1.41 (d, 6H), 3.47 (m, 1H),4.50 (s, 2H), 6.28 (s, 1H), 7.20 (d, 1H), 7.24-7.39 (m, 4H), 7.53 (d,2H), 7.59 (d, 1H), 8.09 (d, 2H), 8.27 (s, 1H) LRMS: m/z ES 607 [MNa]⁺

Example 32N-[3-tert-Butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

The title compound was prepared from the product of example 10, using amethod similar to that described for example 24, as a white powder in46% yield.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.24 (s, 9H), 1.35 (d, 6H), 3.56 (m, 1H),4.41 (d, 2H), 6.22 (s, 1H), 6.85 (d, 2H), 7.03 (m, 1H), 7.12 (dd, 1H),7.19-7.34 (m, 6H), 7.71 (d, 1H), 8.15 (s, 1H), 8.60 (s, 1H), 9.74 (s,1H); LRMS: m/z API-ES 556.4 [MH]⁺

Example 33N-[3-tert-Butyl-1-(3-chloro-4-methoxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]-benzyl}urea

The title compound was prepared from the products of preparations 94 and43, using the same method as that described for preparation 121. Thecrude compound was purified by column chromatography on silica gel,eluting with dichloromethane:7M methanolic ammonia, 100:0 to 97.5:2.5.This was followed by further purification using reversed phase columnchromatography on C18 silica gel, eluting with water/7M methanolicammonia (98:2):acetonitrile/7M methanolic ammonia (98:2), 75:25 to25:75, to afford the desired product as a white solid in 22% yield.

¹H NMR (300 MHz, CDCl₃) δ: 1.25-1.47 (m, 15H), 3.15 (m, 1H), 3.79 (s,3H), 4.55 (d, 2H), 6.30 (s, 1H), 6.67 (d, 1H), 6.81 (m, 2H), 7.07 (m,1H), 7.17-7.31 (m, 4H), 7.36 (m, 1H), 7.42 (m, 1H), 7.66 (s, 1H), 7.94(m, 1H); LCMS m/z 604/606 [M+H]⁺

Example 34N-(3-tert-Butyl-1-pyridin-3-yl-1H-pyrazol-5-yl)-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}-urea

The title compound was prepared from the products of preparations 90 and43, using a similar method to that described for preparation 121. Thecrude compound was purified by column chromatography using a Biotage®silica gel cartridge, eluting with dichloromethane:methanol:0.88ammonia, 100:0:0 to 95:5:0.5. The residue was further purified by columnchromatography on silica gel, eluting with ethyl acetate:methanol,90:10, to afford the desired product in 5% yield.

¹HNMR (400 MHz, CD₃OD) δ: 1.32 (s, 9H), 1.42 (d, 6H), 3.49 (m, 1H), 4.50(s, 2H), 6.29 (s, 1H), 7.21 (d, 1H), 7.26-7.40 (m, 4H), 7.54 (m, 1H),7.61 (d, 1H), 7.96 (d, 1H), 8.31 (s, 1H), 8.55 (d, 1H), 8.74 (s, 1H);LRMS APCI m/z 541 [M+H]⁺

Example 35N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chloro-3-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 21 and216, using the same method as that described for preparation 121. Thecrude compound was triturated with diethyl ether to afford the desiredproduct as a solid in 56% yield.

¹HNMR (300 MHz, CDCl₃) δ: 1.29 (s, 9H), 2.27 (s, 3H), 3.96 (s, 3H), 4.51(d, 2H), 5.79 (s, 1H), 6.24 (s, 1H), 6.58 (s, 1H), 6.97 (m, 1H),7.07-7.38 (m, 10H), 7.41-7.49 (m, 1H), 7.52 (m, 1H), 7.70 (s, 1H); LCMSm/z 652.6 [M+H]⁺

Example 36N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-chloro-3-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of example 36, using asimilar method to that described for example 72. The crude compound wasre-crystallised from dichloromethane/methanol:diethyl ether, as a solidin 23% yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.29 (s, 9H), 2.34 (s, 3H), 4.35 (d, 2H),6.21 (m, 1H), 6.95 (m, 1H), 7.11 (m, 1H), 7.20-7.36 (m, 1H), 7.88 (m,1H), 8.01 (m, 1H), 8.22 (m, 1H), 10.67 (s, 1H); LCMS m/z 638.6[M+H]⁺

Example 37N-{1-[3-(2-Hydroxyethoxy)phenyl]-3-[1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]-benzyl}urea

para-Toluenesulfonic acid (20 mg) was added to a solution of the productof preparation 173 (72 mg, 0.1 mmol) in methanol (10 mL) and the mixturewas stirred at room temperature for 18 hours. The reaction mixture wasthen diluted with ethyl acetate, washed with sodium hydrogen carbonatesolution, dried over magnesium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel,eluting with ethyl acetate:methanol, 100:0 to 90:10, afforded the titlecompound as a white solid in 98% yield, 62 mg.

¹HNMR (400 MHz, DMSO-d₆) δ:1.34 (d, 6H), 1.57 (s, 6H), 1.89 (s, 3H),3.56 (m, 1H), 3.71 (m, 2H), 4.02 (m, 2H), 4.41 (d, 2H), 4.88 (t, 1H),6.36 (s, 1H), 6.97 (d, 1H), 7.03 (m, 2H), 7.09 (m, 2H), 7.24 (m, 2H),7.29 (m, 2H), 7.39 (m, 1H), 7.69 (d, 1H), 8.06 (s, 1H), 8.38 (s, 1H);LRMS APCI m/z 632 [M+H]⁺

Example 38 to 42

The following compounds, of the general formula shown below wereprepared by a method similar to that described for example 37, using theappropriate starting material and para-toluenesulfonic acid.

No. Data Yield A = C(CH₃)₃ 38 X = 3-(2-hydroxyethoxy), R³ =2-chlorophenyl 77% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.23(s, 9 H), 3.70(q, 2H), 4.00(t, 2 H), 4.37(d, 2 H), 4.83(t, 1 H), 6.23(s, 1 H), 6.94(d, 1H), 6.98(m, 1 H), 7.03(m, 2 H), 7.21-7.30(m, 5 H), 7.35(m, 1 H), 7.55(m,1 H), 7.63-7.72(m, 3 H), 7.88(d, 1 H), 8.02(s, 1 H), 8.26(s, 1 H); LRMSAPCI m/z 668 [M + H]⁺ 39 X = 4-(2-hydroxyethoxy), R³ = 2-chlorophenyl51% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.22(s, 9 H), 3.72(q, 2 H), 4.01(t, 2 H),4.35(d, 2 H), 4.85(t, 1 H), 6.19(s, 1 H), 6.93(d, 1 H), 7.01(d, 2 H),7.21-7.33(m, 7 H), 7.55(m, 1 H), 7.63-7.72(m, 3 H), 7.88(d, 1 H),8.01(s, 1 H), 8.13(s, 1 H); LRMS APCI m/z 668 [M + H]⁺ A =(CH₃—S)C(CH₃)₂ 40 X = 3-(2-hydroxyethoxy), R³ = 2-chlorophenyl 65%¹HNMR(400 MHz, DMSO-d₆) δ: 1.57(s, 6 H), 1.89(s, 3 H), 3.70(q, 2 H),4.01(t, 2 H), 4.37(d, 2 H), 4.84(t, 1 H), 6.34(s, 1 H), 6.97(d, 1 H),7.02(m, 3 H), 7.22-7.31(m, 5 H), 7.38(m, 1 H), 7.56(m, 1 H),7.63-7.72(m, 3 H), 7.88 (d, 1 H), 8.02(s, 1 H), 8.32(s, 1 H) 41 X =3-(2-hydroxyethoxy), R³ = 2-methoxyphenyl 80% ¹HNMR(300 MHz, DMSO-d₆) δ:1.58(s, 6 H), 1.90(s, 3 H), 3.69(m, 5 H), 4.01(t, 2 H), 4.37(d, 2 H),4.87(t, 1 H), 6.32(s, 1 H), 6.95(d, 1 H), 7.02(m, 2 H), 7.20(m, 8 H),7.38(m, 1 H), 7.58(m, 2 H), 7.84(m, 2 H), 8.46(s, 1 H); LCMS m/z 696[M + H]⁺ 42 X = 3-(2-hydroxyethoxy), R³ = 2-fluorophenyl 83% ¹HNMR(300MHz, DMSO-d₆) δ: 1.58(s, 6 H), 1.90(s, 3 H), 3.69(m, 2 H), 4.00(t, 2 H),4.35(d, 2 H), 4.91(t, 1 H), 6.28(s, 1 H), 6.91(d, 1 H), 7.05(m, 2 H),7.28(m, 8 H), 7.44(m, 2 H), 7.67(m, 1 H), 7.85(d, 1 H), 8.19(d, 1 H),9.08(s, 1 H); LCMS m/z 684 [M + H]⁺

Example 43N-{3-tert-Butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-fluorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

A solution of the product of preparation 219 (215 mg, 0.29 mmol) wasdissolved in a mixture of acetic acid (4 mL), tetrahydrofuran (2 mL) andwater (1 mL) and the resulting solution was heated to 60° C. for 18hours. The reaction mixture was then concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 99:1 to 92:8. The appropriate fractionswere evaporated under reduced pressure and the residue was trituratedwith dichloromethane/diethyl ether, to afford the title compound as awhite powder in 26% yield, 50.2 mg.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.24 (s, 9H), 3.68 (m, 2H), 3.98 (m, 2H),4.37 (m, 2H), 4.85 (t, 1H), 6.22 (s, 1H), 6.92 (m, 1H), 7.00-7.11 (m,3H), 7.21-7.44 (m, 8H), 7.65 (m, 1H), 7.78 (m, 1H), 7.87 (m, 1H), 8.19(m, 1H), 8.35 (s, 1H); LCMS m/z 652.6 [M+H]⁺

Example 44N-{3-tert-Butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-isopropylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 221,using the same method as that described for example 43, as a whitepowder in 66% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.07 (d, 6H), 1.24 (s, 9H), 2.75 (m, 1H),3.68 (m, 2H), 4.00 (m, 2H), 4.35 (m, 2H), 4.86 (t, 1H), 6.21 (s, 1H),6.90 (m, 1H), 7.01 (m, 3H), 7.16-7.36 (m, 7H), 7.47 (m, 1H), 7.58 (m,2H), 7.86 (m, 2H), 8.31 (s, 1H); LCMS m/z 676.2 [M+H]⁺

Example 45N-{3-tert-Butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 222,using the same method as that described for example 43, as a whitepowder in 45% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.25 (s, 9H), 2.75 (m, 1H), 3.68-3.70 (m,5H), 4.01 (m, 2H), 4.35 (m, 2H), 4.86 (t, 1H), 6.22 (s, 1H), 6.94 (m,1H), 7.01 (m, 3H), 7.13-7.34 (m, 8H), 7.57 (m, 2H), 7.85 (m, 2H), 8.31(s, 1H); LCMS m/z 664.6 [M+H]⁺

Example 46N-[3-tert-Butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

Boron tribromide (1M in dichloromethane, 1 mL, 1 mmol) was addeddropwise to an ice-cold solution of the product of preparation 121 (186mg, 0.27 mmol) in dichloromethane (10 mL) and the mixture was stirredfor 10 minutes at 0° C. The reaction mixture was then diluted withdichloromethane (25 mL) and water (25 mL) and stirring continued at 0°C. for a further 10 minutes. 0.88 Ammonia (5 mL) was added and theaqueous layer was separated and extracted with dichloromethane (2×25mL). The combined organic solution was dried over magnesium sulfateconcentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with ethyl acetate:methanol, 100:0to 95:5. The appropriate fractions were evaporated under reducedpressure and the residue was re-crystallised from ethyl acetate toafford the title compound as a pale yellow solid in 48% yield, 78 mg.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.23 (s, 9H), 4.35 (d, 2H), 6.23 (s, 1H),6.96 (m, 1H), 7.00 (t, 1H), 7.05 (d, 1H), 7.04-7.55 (m, 7H), 7.43 (m,1H), 7.48 (dd, 2H), 7.54 (dd, 1H), 7.83 (d, 1H), 8.05 (s, 1H), 8.28 (s,1H), 10.44 (s, 1H); LRMS APCI m/z 608 [M+H]⁺

Examples 47 to 69

The following compounds, of the general formula shown below wereprepared by a method similar to that described for example 46, using theappropriate starting material and 4-6 equivalents of boron tribromide.

No. Data Yield A = C(CH₃)₃ 47 X = 3-F; R³ = 2-(hydroxyphenyl) 30%¹HNMR(400 MHz, DMSO-d₆) δ: 1.24(s, 9 H), 4.36(d, 2 H), 6.26(s, 1 H),7.02(m, 3 H), 7.19-7.25(m, 6 H), 7.35 (d, 2 H), 7.43(m, 1 H), 7.49(m, 1H), 7.54(dd, 1 H), 7.83 (d, 1 H), 8.06(s, 1 H), 8.39(brs, 1 H), 10.45(s,1 H); LRMS APCI m/z 608 [M + H]⁺ 48 X = 4-CH₂CH₃; R³ = 2-(hydroxyphenyl)58% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.18(t, 3 H), 1.23(s, 9 H), 2.63(q, 2 H),4.36(d, 2 H), 6.23(s, 1 H), 7.01(m, 2 H), 7.05 (d, 1 H), 7.17-7.36(m, 9H), 7.43(m, 1 H), 7.54(d, 1 H), 7.83(d, 1 H), 8.06(s, 1 H), 8.26(s, 1H), 10.46(s, 1 H); LRMS APCI m/z 618 [M + H]⁺ 49 X = 3-CH₂CH₃; R³ =2-(hydroxyphenyl) 64% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.17(t, 3 H), 1.23(s, 9H), 2.63(q, 2 H), 4.36(d, 2 H), 6.24(s, 1 H), 7.00(m, 2 H), 7.05 (d, 1H), 7.19-7.29(m, 8 H), 7.37(m, 1 H), 7.43(m, 1 H), 7.54(d, 1 H), 7.83(d,1 H), 8.06(s, 1 H), 8.27(s, 1 H), 10.46 (s, 1 H); LRMS APCI m/z 618 [M +H]⁺ 50 X = 3-Cl, 4-Cl; R³ = 2-(hydroxyphenyl) 31% ¹HNMR(400 MHz, CD₃OD)δ: 1.31(s, 9 H), 4.48(d, 2 H), 6.26(s, 1 H), 6.97(d, 1 H), 7.03(m, 1 H),7.27(m, 2 H), 7.31-7.39(m, 3 H), 7.45(m, 2 H), 7.54-7.59(m, 2 H), 7.70-7.74(m, 2 H), 7.82(s, 1 H); LRMS APCI m/z 658 [M + H]⁺ 51 X = 3-CN; R³ =2-(hydroxyphenyl) 47% ¹HNMR(400 MHz, CD₃OD) δ: 1.32(s, 9 H), 4.48(s, 2H), 6.28(s, 1 H), 6.97(d, 1 H), 7.03(m, 1 H), 7.24-7.38(m, 5 H), 7.44(m,1 H), 7.55(d, 1 H), 7.62(m, 1 H), 7.70-7.72 (m, 2 H), 7.81-7.82(m, 2 H),7.88(s, 1 H); LRMS APCI m/z 615 [M + H]⁺ 52 X = 4-CN; R³ =2-(hydroxyphenyl) 60% ¹HNMR(400 MHz, CD₃OD) δ: 1.31(s, 9 H), 4.48(s, 2H), 6.29(s, 1 H), 6.97(d, 1 H), 7.02(m, 1 H), 7.26-7.46(m, 6 H), 7.54(d,1 H), 7.70-7.71(m, 3 H), 7.76-7.79(m, 2 H), 7.82(s, 1 H); LRMS APCI m/z615 [M + H]⁺ 53 X = H; R³ = 2-(hydroxyphenyl) 83% ¹HNMR(400 MHz, CD₃OD)δ: 1.31(s, 9 H), 4.48(s, 2 H), 6.29(s, 1 H), 6.98-7.04(m, 2 H),7.23-7.33(m, 4 H), 7.36 (m, 1 H), 7.40-7.49(m, 6 H), 7.54(d, 1 H),7.69(d, 1 H), 7.81(s, 1 H); LRMS APCI m/z 590 [M + H]⁺ 54 X = 3-OH; R³ =2-chlorophenyl 48% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.22(s, 9 H), 4.37(d, 2H), 6.21(s, 1 H), 6.75(d, 1 H), 6.86(d, 1 H), 6.87(s, 1 H), 6.89(m, 1H), 7.22-7.30(m, 6 H), 7.55(m, 1 H), 7.63-7.72 (m, 3 H), 7.88(d, 1 H),8.02(s, 1 H), 8.24(s, 1 H), 9.70(s, 1 H) 55 X = 3-OH; R³ =2-(hydroxyphenyl) 50% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.13(s, 9 H), 4.40(d, 2H), 6.23(s, 1 H), 6.76(d, 1 H), 6.89(s, 2 H), 6.95-7.10 (m, 3 H),7.16-7.28(m, 6 H), 7.40(m, 1 H), 7.55(d, 1 H), 7.77-7.90(m, 1 H),8.06(s, 1 H), 8.65(s, 1 H); LRMS APCI m/z 606 [M + H]⁺ 56 X = 3-OH; R³ =2-methylphenyl 57% ¹HNMR(400 MHz, CDCl₃) δ: 1.29(s, 9 H), 2.14(s, 3 H),4.48(d, 2 H), 6.36(s, 1 H), 6.47(d, 1 H), 6.56(brs, 1 H), 6.75(s, 1 H),6.80(d, 1 H), 6.95(m, 2 H), 7.17(m, 2 H), 7.33(m, 7 H), 7.42(m, 1 H),7.60(s, 1 H), 7.72(brs, 1 H); LRMS APCI m/z 604 [M + H]⁺ 57 X = 3-OH,5-CH₃; R³ = HC(CH₃)₂ 59% ¹HNMR(300 MHz, DMSO-d₆) δ: 1.35(d, 6 H),3.56(m, 1 H), 4.38(d, 2 H), 6.19(s, 1 H), 6.96-7.04(m, 2 H), 7.09 (dd, 1H), 7.17-7.30(m, 5 H), 7.39(d, 1 H), 7.68(d, 1 H), 8.22(s, 1 H), 8.58(s,1 H), 10.53(s, 1 H); LCMS m/z 590/592 [M + H]⁺ 58 X = 3-CH₃; R³ =2-hydroxy-5-chlorophenyl 39% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.22(s, 9 H),2.31(s, 3 H), 4.37(d, 2 H), 6.22(s, 1 H), 7.00(m, 1 H), 7.05(d, 1 H),7.20(m, 8 H), 7.33(m, 1 H), 7.45(d, 1 H), 7.54(s, 1 H), 7.83(d, 1 H),8.10(s, 1 H), 8.27(s, 1 H), 10.75(s, 1 H); LRMS APCI m/z 638/640 [M +H]⁺ A = (CH₃—S—CH₂)C(CH₃)₂ 59 X = 3-(2-hydroxyethoxy), R³ =2-(hydroxyphenyl) 63% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.28(s, 6 H), 1.96(s, 3H), 2.76(s, 2 H), 3.70(m, 2 H), 4.00(t, 2 H), 4.37(d, 2 H), 4.88(brs, 1H), 6.28(s, 1 H), 6.94(d, 1 H), 7.02(m, 5 H), 7.19(m, 3 H), 7.27(m, 2H), 7.37(m, 1 H), 7.43(m, 1 H), 7.54(d, 1 H), 7.84(d, 1 H), 8.06(s, 1H), 8.37(s, 1 H), 10.47 (brs, 1 H); LRMS ESI m/z 696 [M + H]⁺ 60 X = H,R³ = 2-(hydroxyphenyl) 47% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.39(s, 6 H),2.00(s, 3 H), 2.83(s, 2 H), 4.56(d, 2 H), 6.35(s, 1 H), 6.85(brm, 1 H),6.92(m, 1 H), 7.00(d, 1 H), 7.12-7.52(m, 14 H), 7.74 (brm, 1 H); LRMSESI m/z 636 [M + H]⁺ 61 X = 4-CH₃, R³ = 2-(hydroxyphenyl) 49% ¹HNMR(400MHz, DMSO-d₆) δ: 1.39(s, 6 H), 2.00(s, 3 H), 2.18(s, 3 H), 2.84(s, 2 H),4.56(d, 2 H), 6.35(s, 1 H), 6.87(brm, 1 H), 6.93(m, 1 H), 7.01-7.05(m, 3H), 7.15(d, 1 H), 7.20-7.52(m, 10 H), 7.72(brm, 1 H); LRMS ESI m/z 650[M + H]⁺ 62 X = 4-F; R³ = 2-(hydroxyphenyl) 32% ¹HNMR(400 MHz, CD₃OD) δ:1.37(s, 6 H), 1.99(s, 3 H), 2.82(s, 2 H), 4.49(s, 2 H), 6.31(s, 1 H),7.01(m, 2 H), 7.15- 7.49(m, 10 H), 7.55(d, 1 H), 7.71(d, 1 H), 7.82(s, 1H); LRMS APCI m/z 654 [M + H]⁺ 63 X = 3-F; R³ = 2-(hydroxyphenyl) 34%¹HNMR(400 MHz, CD₃OD) δ: 1.38(s, 6 H), 1.99(s, 3 H), 2.83(s, 2 H),4.50(s, 2 H), 6.31(s, 1 H), 6.98(d, 1 H), 7.03 (m, 1 H), 7.14(m, 1 H),7.23-7.33(m, 6 H), 7.37(d, 1 H), 7.41-7.50(m, 2 H), 7.55(d, 1 H),7.71(d, 1 H), 7.80(s, 1 H); LRMS APCI m/z 654 [M + H]⁺ 64 X = 3-F, 4-F;R³ = 2-(hydroxyphenyl) 19% ¹HNMR(400 MHz, CDCl₃) δ: 1.38(s, 6 H),1.99(s, 3 H), 2.79(s, 2 H), 4.50(s, 2 H), 6.22(s, 1 H), 6.97(m, 2 H),7.15- 7.28(m, 6 H), 7.30-7.41(m, 5 H), 7.45(d, 1 H), 7.55(m, 1 H),7.78(m, 1 H); LRMS APCO m/z 672 [M + H]⁺ 65 X = 3-OH; R³ = CH(CH₃)₂ 53%¹HNMR(400 MHz, DMSO-d₆) δ: 1.28(s, 6 H), 1.34(d, 6 H), 1.96(s, 3 H),2.76(s, 2 H), 3.56(m, 1 H), 4.40(d, 2 H), 6.26(s, 1 H), 6.77(d, 1 H),6.87(m, 2 H), 7.04(m, 1 H), 7.11(d, 1 H), 7.24(m, 2 H), 7.30(m, 3 H),7.70(d, 1 H), 8.32(s, 1 H), 8.60(s, 1 H), 9.76(s, 1 H); LRMS APCI m/z602 [M + H]⁺ 66 X = 4-OH; R³ = CH(CH₃)₂ 58% ¹HNMR(400 MHz, DMSO-d₆) δ:1.27(s, 6 H), 1.34(d, 6 H), 1.95(s, 3 H), 2.74(s, 2 H), 3.55(m, 1 H),4.39(d, 2 H), 6.23(s, 1 H), 6.84(d, 2 H), 7.00(m, 1 H), 7.11(d, 1 H),7.18 (d, 2 H), 7.24(m, 2 H), 7.28(m, 2 H), 7.69(d, 1 H), 8.15(s, 1 H),8.59(s, 1 H), 9.73(s, 1 H); LRMS APCI m/z 602 [M + H]⁺ A =(CH₃—S)C(CH₃)₂ 67 X = 3-CF₃; R³ = 2-(hydroxyphenyl) 57% ¹HNMR(400 MHz,CDCl₃) δ: 1.65(s, 6 H), 1.95(s, 3 H), 4.56(d, 2 H), 6.40(d, 1 H),6.90-7.00(m, 2 H), 7.10(brs, 1 H), 7.20-7.45(m, 8 H), 7.55(m, 2 H),7.70(d, 1 H), 7.80 (brs, 1 H), 7.90(s, 1 H), 8.10(brs, 1 H); LRMS APCIm/z 780 [M + H]⁺ 68 X = 4-OH; R³ = 2-(hydroxyphenyl) 66% ¹HNMR(400 MHz,DMSO-d₆) δ: 1.55(s, 6 H), 1.87(s, 3 H), 4.37(d, 2 H), 6.30(s, 1 H),6.86(d, 2 H), 7.00-7.10(m, 3 H), 7.20-7.27(m, 7 H), 7.41(m, 1 H),7.55(d, 1 H), 7.82 (d, 1 H), 8.09(s, 1 H), 8.20(s, 1 H), 9.80(brs, 1 H),10.42 (brs, 1 H); LRMS APCI m/z 780 [M + H]⁺ 69 X = 3-Br; R³ =2-(hydroxyphenyl) 42% ¹HNMR(400 MHz, DMSO-d₆) δ: 1.58(s, 6 H), 1.88(s, 3H), 4.35(d, 2 H), 6.35(s, 1 H), 7.00-7.07(m, 3 H), 7.19- 7.26(m, 5 H),7.40-7.46(m, 2 H), 7.50-7.60(m, 3 H), 7.69 (s, 1 H), 7.83(d, 1 H),8.06(s, 1 H), 8.45(s, 1 H), 10.42(s, 1 H); LRMS ESI m/z 702 [M + H]⁺^(a)crude compounds were triturated with diethyl ether rather thanre-crystallisation from ethyl acetate.

Example 48: Crude compound was further purified by column chromatographyon silica gel, eluting with ethyl acetate:methanol, 100:0 to 95:5,followed by trituration of the residue with diethyl ether.

Example 66: Crude compound was re-crystallised from ethylacetate/methanol

Example 70N-(3-tert-Butyl-1-pyridin-3-yl-1H-pyrazol-5-yl)-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 167,using the same method as that described for example 46, in 75% yield.

¹HNMR (400 MHz, CD₃OD) δ: 1.32 (s, 9H), 4.48 (s, 2H), 6.30 (s, 1H), 7.01(m, 2H), 7.24-7.37 (m, 5H), 7.44 (m, 1H), 7.54 (m, 2H), 7.71 (d, 1H),7.84 (s, 1H), 7.97 (d, 1H), 8.52 (d, 1H), 8.73 (s, 1H); LRMS APCI m/z591 [M+H]⁺

Example 71N-(3-tert-Butyl-1-pyridin-2-yl-1H-pyrazol-5-yl)-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 168,using the same method as that described for example 46, as a brown solidin 18% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.25 (s, 9H), 4.46 (s, 2H), 6.49 (s, 1H),7.00 (m, 1H), 7.23-7.30 (m, 5H), 7.40-7.45 (m, 2H), 7.54 (d, 1H),7.83-7.86 (m, 2H), 7.94-8.00 (m, 1H), 8.05 (m, 1H), 8.11 (s, 1H), 8.35(m, 1H), 10.45 (s, 1H), 10.99 (s, 1H); LRMS APCI m/z 591 [M+H]⁺

Example 72N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

Boron tribromide (1M in dichloromethane, 5.05 mL, 5.05 mmol) was addeddropwise to a solution of the product of preparation 124 (0.18 g, 0.25mmol) in dichloromethane (2 mL) and the mixture was stirred for 18 hoursat room temperature. The reaction mixture was then diluted with water(1.5 mL) and stirring continued for a further 10 minutes before1,2-diaminoethane (1.5 mL) was added. The mixture was then stirredvigorously and acidified to pH1 with 6M hydrochloric acid. The aqueouslayer was separated and re-extracted with dichloromethane (5 mL) and thecombined organic solution was dried over magnesium sulfate andconcentrated in vacuo. Re-crystallisation of the residue fromdichloromethane:methanol, 50:50, afforded the title compound as a whitesolid in 36% yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.29 (s, 9H), 2.34 (s, 3H), 4.39 (d, 2H),6.25 (s, 1H), 7.02-7.59 (m, 14H), 7.81-7.91 (m, 1H), 8.08 (s, 1H), 8.28(s, 1H), 10.53 (s, 1H); LCMS m/z 604.6 [M+H]⁺

Examples 73 to 79

The following compounds, of the general formula shown below wereprepared by a method similar to that described for example 72, using theappropriate starting material and 4-6 equivalents of boron tribromide.

No. Data Yield A = C(CH₃)₃ 73 X = 3-Cl, 4-OH; R³ = HC(CH₃)₂ 59%¹HNMR(400 MHz, CDCl₃) δ: 1.23(s, 9 H), 1.35(d, 6 H), 3.56(m, 1 H),4.38(d, 2 H), 6.19(s, 1 H), 6.96-7.04(m, 2 H), 7.09(dd, 1 H),7.17-7.30(m, 5 H), 7.39(d, 1 H), 7.68 (d, 1 H), 8.22(s, 1 H), 8.58(s, 1H); LRMS API-ES 590/592 [M + H]⁺ 74 X = 3-CH₂CH₃,4-OH; R³ = HC(CH₃)₂ 90%¹HNMR(300 MHz, DMSO-d₆) δ: 1.14(t, 3 H), 1.24(s, 9 H), 1.35(s, 6 H),2.56(q, 2 H), 3.57(m, 1 H), 4.40(d, 2 H), 6.19 (s, 1 H), 6.86(d, 1 H),7.00-7.14(m, 4 H), 7.22-7.30(m, 4 H), 7.68(d, 1 H), 8.13(s, 1 H),8.59(s, 1 H), 9.63(s, 1 H); LCMS m/z 584 [M + H]⁺ 75 X = 3-OH, 4-CH₂CH₃;R³ = HC(CH₃)₂ 33% ¹HNMR(300 MHz, DMSO-d₆) δ: 1.15(t, 3 H), 1.24(s, 9 H),1.35(s, 6 H), 2.56(q, 2 H), 3.56(m, 1 H), 4.41(d, 2 H), 6.22 (s, 1 H),6.79(dd, 1 H), 6.89(d, 1 H), 7.03-7.15(m, 3 H), 7.19-7.31(m, 3 H),7.69(d, 1 H), 8.27(s, 1 H), 8.59(s, 1 H), 9.65(s, 1 H); LCMS m/z 584[M + H]⁺ 76 X = 3-OH, 4-Cl; R³ = HC(CH₃)₂ 84% ¹HNMR(300 MHz, DMSO-d₆) δ:1.24(s, 9 H), 1.35(d, 6 H), 3.56(m, 1 H), 4.40(d, 2 H), 6.23(s, 1 H),6.88(d, 1 H), 6.91(m, 1 H), 7.09(m, 2 H), 7.22-7.37(m, 4 H), 7.40-7.67(m, 1 H), 7.70(d, 1 H), 8.31(s, 1 H), 8.57(s, 1 H), 10.52(s, 1 H);LCMS m/z 590/592 [M + H]⁺ 77 X = 3-F, 4-F; R³ = 2-chloro-4-hydroxyphenyl27% ¹HNMR(300 MHz, CDCl₃) δ: 1.24(s, 9 H), 4.35(d, 2 H), 6.23(s, 1 H),6.89-7.01(m, 3 H), 7.17-7.51(m, 6 H), 7.54- 7.62(m, 3 H), 7.84(m, 1 H),7.97(s, 1 H), 8.34(s, 1 H); LCMS m/z 660.6 [M + H]⁺ 78 X = 3-F, 4-F; R³= 2-chloro-5-hydroxyphenyl 72% ¹HNMR(300 MHz, CDCl₃) δ: 1.24(s, 9 H),4.35(d, 2 H), 6.23(s, 1 H), 6.89-7.00(m, 3 H), 7.17-7.45(m, 6 H), 7.48-7.62(m, 3 H), 7.81(m, 1 H), 7.97(s, 1 H), 8.34(s, 1 H); LCMS m/z 660.6[M + H]⁺ 79 X = 3-F, 4-F; R³ = 2-hydroxyphenyl 26% ¹HNMR(300 MHz, CD₃OD)δ: 1.30(s, 9 H), 4.48(d, 2 H), 6.24(s, 1 H), 6.97(m, 1 H), 7.31(m, 6 H),7.34(s, 1 H), 7.40 (m, 2 H), 7.52(dd, 1 H), 7.70(d, 1 H), 7.80(s, 1 H);LCMS m/z 624 [M + H]⁺

Example 73: The crude compound was further purified byre-crystallisation from dichloromethane/methanol: diethyl ether

Example 74: The crude compound was purified by column chromatography onsilica gel, eluting with dichloromethane:methanol, 98:2 to 92:8

Example 75: The crude compound was re-crystallised fromdichloromethane/methanol:diethyl ether

Example 78: The crude compound was purified by column chromatography onsilica gel, eluting with dichloromethane:methanol, 97:3 to 94:6,followed by trituration with dichloromethane/methanol:diethyl ether (×3)

Example 79: The crude compound was purified by column chromatography onsilica gel, eluting with dichloromethane:methanol, 100:0 to 95:5,followed by trituration with dichloromethane

Example 80N-{3-tert-Butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

Boron tribromide (1M in dichloromethane, 1.6 mL, 1.6 mmol) was addeddropwise to a solution of the product of preparation 122 (270 mg, 0.33mmol) in dichloromethane (10 mL), cooled to −78° C. and the mixture wasstirred for 90 minutes at this temperature. The reaction mixture wasstirred for a further 30 minutes, allowing the temperature to rise to25° C., and was then quenched with methanol (10 mL) and 0.88 ammonia (3mL). The mixture was acidified with 2M hydrochloric acid and extractedwith dichloromethane (3×50 mL). The combined organic solution was driedover magnesium sulfate, concentrated in vacuo and the residue waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 90:10. The appropriate fractions wereevaporated under reduced pressure and the residue was re-crystallisedfrom ethyl acetate/methanol to afford the title compound as a solid in56% yield, 120 mg.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.24 (s, 9H), 3.70 (m, 2H), 4.00 (t, 2H),4.37 (d, 2H), 4.86 (m, 1H), 6.25 (s, 1H), 6.94 (dd, 1H), 7.03 (m, 5H),7.19 (m, 3H), 7.26 (d, 2H), 7.36 (t, 1H), 7.54 (d, 1H), 7.83 (d, 1H),8.06 (s, 1H), 8.32 (s, 1H), 10.45 (s, 1H); LRMS APCI m/z 650 [M+H]⁺

Example 81N-[3-tert-Butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

Boron tribromide (1M in dichloromethane, 1.3 mL, 1.3 mmol) was addeddropwise to a solution of the product of preparation 174 (214 mg, 0.26mmol) in dichloromethane (10 mL), at −78° C., and the mixture wasstirred for 5 minutes at this temperature. The reaction mixture was thenstirred for a further 5 minutes allowing the temperature to warm to 0°C. The mixture was re-cooled to −78° C., quenched with methanol (5 mL)and the temperature was allowed to rise to 25° C. The reaction mixturewas then diluted with water and extracted with dichloromethane (3×40mL). The combined organic solution was dried over magnesium sulfate,concentrated in vacuo and the residue was purified by columnchromatography on silica gel, eluting with dichloromethane:methanol:0.88ammonia, 100:0:0 to 93:7:1. The appropriate fractions were evaporatedunder reduced pressure and the residue was re-crystallised from ethylacetate/methanol to afford the title compound as a solid in 47% yield,79 mg.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.23 (s, 9H), 3.52 (m, 2H), 4.06 (t, 2H),4.36 (d, 2H), 4.72 (t, 1H), 6.22 (s, 1H), 6.76 (d, 1H), 6.88 (m, 2H),7.01 (t, 1H), 7.14 (t, 1H), 7.17-7.28 (m, 7H), 7.58 (m, 2H), 7.82 (d,1H), 8.12 (s, 1H), 8.28 (s, 1H), 9.73 (s, 1H); LRMS APCI m/z 650 [M+H]⁺

Example 82N-{1-(4-Ethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 157,using the same method as that described for example 81, as a solid in60% yield.

¹HNMR (400 MHz, CDCl₃) δ: 1.19 (t, 3H), 1.57 (s, 6H), 1.88 (s, 3H), 2.64(q, 2H), 4.37 (d, 2H), 6.34 (s, 1H), 7.03 (m, 3H), 7.18-7.37 (m, 9H),7.43 (m, 1H), 7.54 (d, 1H), 8.06 (s, 1H), 8.32 (s, 1H), 10.46 (s, 1H);LRMS APCI m/z 650 [M+H]⁺

Example 83N-{1-(3-Ethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 158,using the same method as that described for example 81. The crudecompound was triturated with ethyl acetate/dichloromethane to afford thedesired product as a solid in 52% yield.

¹HNMR (400 MHz, CDCl₃) δ: 1.17 (t, 3H), 1.57 (s, 6H), 1.89 (s, 3H), 2.64(q, 2H), 4.37 (d, 2H), 6.35 (s, 1H), 7.01 (m, 3H), 7.05 (d, 1H),7.19-7.29 (m, 8H), 7.39 (m, 1H), 7.44 (d, 1H), 7.54 (d, 1H), 8.06 (s,1H), 8.33 (s, 1H), 10.45 (s, 1H); LRMS APCI m/z 650 [M+H]⁺

Example 84N-(2-{[3-(2-Hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-(4-methoxy-3-methylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

The title compound was prepared from the product of preparation 159,using the same method as that described for example 81. The crudecompound was triturated with ethyl acetate to afford the desired productas a solid in 43% yield.

¹HNMR (400 MHz, CDCl₃) δ: 1.56 (s, 6H), 1.88 (s, 3H), 2.17 (s, 3H), 3.81(s, 3H), 4.36 (d, 2H), 6.32 (s, 1H), 6.99-7.06 (m, 4H), 7.18-7.26 (m,7H), 7.43 (m, 1H), 7.54 (d, 1H), 7.83 (d, 1H), 8.06 (s, 1H), 8.21 (s,1H), 10.45 (s, 1H); LRMS APCI m/z 666 [M+H]⁺

Example 85N-{1-(3-Chlorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 154,using the same method as that described for example 81. The crudecompound was triturated with ethyl acetate to afford the desired productas a solid in 44% yield,

¹HNMR (400 MHz, CDCl₃) δ: 1.55 (s, 6H), 1.88 (s, 3H), 4.35 (d, 2H), 6.35(s, 1H), 6.87-7.32 (m, 8H), 7.34-7.62 (m, 6H), 7.82 (d, 1H), 8.05 (s,1H), 8.50 (s, 1H), 10.50 (s, 1H); LRMS APCI m/z 608/610 [M+H]⁺

Example 86N-(2-{[3-(5-Chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea

The title compound was prepared from the product of preparation 165,using a similar method to that described for example 81. The crudecompound was triturated with methanol to afford the desired product as asolid in 26% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.56 (s, 6H), 1.87 (s, 3H), 2.34 (s, 3H),4.36 (d, 2H), 6.35 (s, 1H), 7.02 (m, 1H), 7.05 (d, 1H), 7.22 (m, 8H),7.36 (m, 1H), 7.47 (m, 1H), 7.55 (s, 1H), 7.83 (d, 1H), 8.10 (s, 1H),8.31 (s, 1H), 10.75 (s, 1H); LRMS APCI m/z 608/610 [M+H]⁺

Example 87N-(2-{[3-(5-Chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea

The title compound was prepared from the product of preparation 166,using a similar method to that described for example 81. The crudecompound was triturated with ethyl acetate/methanol to afford thedesired product as a solid in 24% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.56 (s, 6H), 1.87 (s, 3H), 2.34 (s, 3H),4.36 (d, 2H), 6.33 (s, 1H), 7.01 (m, 1H), 7.05 (d, 1H), 7.25 (m, 9H),7.47 (m, 1H), 7.54 (s, 1H), 7.83 (d, 1H), 8.11 (s, 1H), 8.27 (s, 1H),10.75 (s, 1H); LRMS APCI m/z 608/610 [M+H]⁺

Example 88N-(2-{[3-(5-Chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-[3-[1,1-dimethyl-2-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea

The title compound was prepared from the product of preparation 149,using a similar method to that described for example 81. The crudecompound was triturated with ethyl acetate/methanol to afford thedesired product as a solid in 52% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.26 (s, 6H), 1.95 (s, 3H), 2.33 (s, 3H),2.77 (s, 2H), 4.36 (d, 2H), 6.27 (s, 1H), 6.98 (m, 1H), 7.06 (d, 1H),7.16-7.35 (m, 9H), 7.47 (d, 1H), 7.55 (s, 1H), 7.84 (d, 1H), 8.12 (s,1H), 8.27 (s, 1H), 10.78 (s, 1H); LRMS APCI m/z 684/686 [M+H]⁺

Example 89N-(2-{[3-(2-Ethylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-(3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

A solution of the product of preparation 228 (280 mg, 0.38 mmol) indichloromethane (6 mL) was cooled to −78° C. Boron tribromide (1M indichloromethane, 1.9 mL, 1.9 mmol) was added dropwise and the mixturewas stirred for 20 minutes. The reaction mixture was then diluted withmethanol (10 mL) and the temperature was allowed to rise to 25° C. Themixture was concentrated in vacuo and the residue was re-dissolved indichloromethane and washed with 0.88 ammonia (2×10 mL). The organicsolution was dried over magnesium sulfate, concentrated in vacuo and theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 99.75:0.25 to 95:5, to afford the titlecompound in 59% yield, 146 mg.

¹HNMR (400 MHz, CDCl₃) δ: 0.96 (t, 3H), 1.59 (s, 6H), 1.88 (s, 3H), 2.38(q, 2H), 4.43 (s, 2H), 6.42-6.45 (m, 2H), 6.76 (m, 2H), 6.85 (m, 1H),6.95 (d, 1H), 7.10-7.37 (m, 8H), 7.37 (m, 1H), 7.45 (m, 1H), 7.54 (s,1H), 8.28 (s, 1H); LRMS APCI m/z 650 [M+H]⁺

Example 90N-{1-(4-Hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 230,using a similar method to that described for example 89, as a solid in10% yield.

¹HNMR (400 MHz, CD₃OD) δ: 1.61 (s, 6H), 1.90 (s, 3H), 2.17 (s, 3H), 4.45(s, 2H), 6.36 (s, 1H), 6.87 (d, 2H), 7.19-7.52 (m, 11H), 7.66 (s, 1H),7.73 (d, 1H); LRMS APCI m/z 636 [M+H]⁺

Example 91N-{1-(3-Hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 160,using a similar method to that described for example 89, as a solid in66% yield.

¹HNMR (400 MHz, CDCl₃) δ: 162 (s, 6H), 1.91 (s, 3H), 2.15 (s, 3H), 4.47(s, 2H), 6.44 (m, 1H), 6.48 (s, 1H), 6.76 (s, 1H), 6.82 (d, 1H), 6.93(m, 2H), 7.04 (d, 1H), 7.18 (m, 1H), 7.24-7.45 (m, 9H), 7.58 (s, 1H),7.98 (s, 1H); LRMS APCI m/z 636 [M+H]⁺

Example 92N-{-(3,5-Dimethylphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 164,using a similar method to that described for example 89. The crudecompound was triturated with ethyl acetate/methanol to afford the titlecompound as a solid in 59% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.37 (s, 6H), 1.89 (s, 3H), 2.30 (s, 6H),4.37 (d, 2H), 6.44 (s, 1H), 7.02 (m, 6H), 7.10 (m, 5H), 7.42 (m, 1H),7.54 (d, 1H), 7.81 (d, 1H), 8.05 (s, 1H), 8.30 (s, 1H), 10.45 (s, 1H);LRMS APCI m/z 650 [M+H]⁺

Example 93N-[3-tert-Butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

Boron tribromide (1M in dichloromethane, 0.74 mL, 0.74 mmol) was addeddropwise to a solution of the product of preparation 229 (107 mg, 0.15mmol) in dichloromethane (5 mL), at −78° C., and the mixture was stirredfor 2 hours at this temperature. The reaction mixture was then quenchedwith methanolic ammonia (7M, 5 mL) and allowed to warm to roomtemperature. The mixture was diluted with water and extracted with ethylacetate, and the organic solution was dried over magnesium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography on silica gel, eluting with ethyl acetate:methanol, 100:0to 90:10, afforded the title compound as a pale yellow solid in 68%yield, 64 mg.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.22 (s, 9H), 2.38 (s, 3H), 4.36 (d, 2H),6.21 (s, 1H), 6.76 (d, 1H), 6.86 (d, 1H), 6.87 (s, 1H), 7.00 (m, 1H),7.23-7.34 (m, 7H), 7.49-7.65 (m, 3H), 7.83 (s, 1H), 7.88 (d, 1H), 9.26(s, 1H), 9.73 (s, 1H); LRMS APCI m/z 636 [M+H]⁺

Example 94N-{1-(4-Fluorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 152,using the same method as that described for example 93, as a solid in41% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.57 (s, 6H), 1.88 (s, 3H), 4.36 (d, 2H),6.34 (s, 1H), 7.01 (m, 2H), 7.05 (d, 1H), 7.17-7.27 (m, 5H), 7.32 (m,2H), 7.43 (m, 1H), 7.48-7.55 (m, 3H), 7.84 (d, 1H), 8.06 (s, 1H), 8.33(s, 1H), 10.44 (s, 1H); LRMS APCI m/z 640 [M+H]⁺

Example 95N-{1-(3,4-Difluorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 156,using the same method as that described for example 93. The crudecompound was further purified by HPLC using a Phenomenex Luna C18system, eluting with acetonitrile:water/trifluoroacetic acid(5.95:0.1):acetonitrile, 100:0 to 0:100, to afford the desired productin 3% yield.

¹HNMR (400 MHz, CDCl₃) δ: 1.65 (s, 6H), 1.94 (s, 3H), 4.52 (d, 2H), 6.40(s, 1H), 6.80 (d, 1H), 6.91 (m, 1H), 7.00 (s, 1H), 7.12 (m, 1H), 7.19(m, 1H), 7.25-7.42 (m, 9H), 7.61 (m, 2H), 8.71 (s, 1H)

Example 96N-{1-(3-Fluorophenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

Boron tribromide (1M in dichloromethane, 0.85 mL, 0.85 mmol) was addeddropwise to a solution of the product of preparation 153 (150 mg, 0.21mmol) in dichloromethane (10 mL), cooled to −40° C., and the mixture wasstirred for 20 minutes at this temperature. The reaction mixture wasthen quenched with methanol (5 mL) diluted with water (30 mL) anddichloromethane (30 mL) and allowed to warm to room temperature. Themixture was basified with 0.88 ammonia (5 mL) and extracted withdichloromethane (3×30 mL). The combined organic solution was dried overmagnesium sulfate, concentrated in vacuo and the residue was purified bycolumn chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 95:5, to afford the title compound asa white solid in 45% yield, 61 mg.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.58 (s, 6H), 1.89 (s, 3H), 4.36 (d, 2H),6.37 (s, 1H), 7.00 (m, 1H), 7.04 (m, 2H), 7.18-7.27 (m, 6H), 7.36 (m,2H), 7.43 (m, 1H), 7.53 (m, 2H), 7.83 (d, 1H), 8.06 (s, 1H), 8.44 (s,1H), 10.44 (s, 1H); LRMS APCI m/z 640 [M+H]⁺

Example 97N-[3-tert-Butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

Boron tribromide (2M in dichloromethane, 0.63 mL, 1.26 mmol) was addeddropwise to a solution of the product of preparation 138 (300 mg, 0.42mmol) in dichloromethane (2.5 mL) cooled to −45° C., and the mixture wasstirred for 45 minutes at this temperature. Further boron tribromide (2Min dichloromethane, 0.63 mL, 1.26 mmol) was then added and the mixturewas stirred for 30 minutes at −45° C. The reaction mixture was thenquenched with dimethylamine (40% in water, 2 mL) and allowed to warm toroom temperature. The mixture was diluted with water (10 mL) anddichloromethane (10 mL) and the biphasic system was acidified with 4Mhydrochloric acid. The aqueous layer was separated and extracted withdichloromethane (3×10 mL), and the combined organic solution was driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel, eluting withdichloromethane:methanol, 100:0 to 90:10, followed by trituration withdichloromethane/diethyl ether, to afford the title compound as a whitesolid in 29% yield, 76.9 mg.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.24 (s, 9H), 3.77 (s, 3H), 4.37 (d, 2H),6.21 (s, 1H), 6.91-7.04 (m, 5H), 7.17-7.41 (m, 8H), 7.51 (dd, 1H), 7.81(d, 1H), 7.92 (s, 1H), 8.03 (s, 1H), 10.60 (brs, 1H); LCMS APCI m/z 620[M+H]⁺

Example 98N-[3-tert-Butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of 139, using the samemethod as that described for example 97. The crude compound was furtherpurified by reverse phase column chromatography on C18 silica gel,eluting with water:acetonitrile, 67:33 to 33:67, followed by triturationwith dichloromethane/diethyl ether to afford the desired product in 11%yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.25 (s, 9H), 3.76 (s, 3H), 4.37 (d, 2H),6.24 (s, 1H), 6.90-7.06 (m, 6H), 7.18-7.25 (m, 5H), 7.32-7.45 (m, 2H),7.53 (d, 1H), 7.82 (s, 1H), 8.04 (s, 1H), 8.33 (s, 1H), 10.40 (brs, 1H);LCMS APCI m/z 620 [M+H]⁺

Example 99N-[3-(1,1-Dimethylpropyl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The product of preparation 141 (203 mg, 0.29 mmol) was suspended inhydrobromic acid (5.7M in glacial acetic acid, 4 mL, 22.8 mmol) and themixture was stirred at room temperature for 18 hours. The reactionmixture was then diluted with saturated sodium hydrogen carbonatesolution and extracted with dichloromethane. The organic solution waswashed with brine, dried over magnesium sulfate and concentrated invacuo. Trituration of the residue with diethyl ether afforded the titlecompound as a white solid in 81% yield, 144 mg.

¹HNMR (400 MHz, DMSO-d₆) δ: 0.73 (t, 3H), 1.17 (s, 6H), 1.54 (q, 2H),2.32 (s, 3H), 4.36 (d, 2H), 6.19 (s, 1H), 6.98-7.06 (m, 2H), 7.15-7.33(m, 10H), 7.45 (m, 1H), 7.55 (d, 1H), 7.85 (d, 1H), 8.06 (s, 1H), 8.24(s, 1H), 10.47 (s, 1H); LRMS ESI m/z 618 [M+H]⁺

Example 100N-{3-(1,1-Dimethylpropyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-2-{[3-(2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 170,using a method similar to that described for example 99, as a solid in21% yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 0.76 (t, 3H), 1.20 (s, 6H), 1.56 (q, 2H),3.70 (s, 2H), 4.01 (t, 2H), 4.37 (d, 2H), 4.86 (s, 1H), 6.21 (s, 1H),6.94 (m, 1H), 7.05 (m, 5H), 7.23 (m, 5H), 7.38 (m, 2H), 7.53 (dd, 1H),7.82 (d, 1H), 8.05 (s, 1H), 8.32 (s, 1H), 10.43 (s, 1H); LCMS m/z 665[M+H]⁺

Example 101N-[3-tert-Butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

A mixture of the product of example 47 (100 mg, 0.17 mmol),2-(2-bromoethoxy)tetrahydro-2H-pyran (30 μL, 0.20 mmol) and potassiumcarbonate (32 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL) was heatedat 60° C. for 18 hours. Further 2-(2-bromoethoxy)tetrahydro-2H-pyran (15μL, 0.10 mmol) was added and the mixture was heated at 60° C. for 6hours. The cooled reaction mixture was then diluted with ethyl acetate(20 mL), washed with water (10 mL) and brine (10 mL), dried overmagnesium sulfate and concentrated in vacuo. The residue was dissolvedin methanol (3 ml) para-toluenesulfonic acid (20 mg) was added and themixture was stirred at room temperature for 48 hours. The reactionmixture was then diluted with ethyl acetate (20 mL), washed with water(3×10 mL), dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel, elutingwith dichloromethane:methanol, 95:5 to 92:8. The residue was furtherpurified by column chromatography on silica gel, eluting with ethylacetate:methanol, 97.5:2.5 to 95:5, to afford the title compound as asolid in 23% yield, 24.5 mg.

¹HNMR (400 MHz, CDCl₃) δ: 1.24 (s, 9H), 3.70 (m, 2H), 4.01 (m, 2H), 4.37(d, 2H), 6.25 (s, 1H), 6.68 (m, 1H), 6.92 (m, 2H), 7.00-7.07 (m, 5H),7.15 (m, 1H), 7.20-7.39 (m, 4H), 7.53 (m, 2H), 7.71 (m, 1H), 7.79 (s,1H)

Example 102N-(2-{[3-(2-Ethylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-[3-(2-hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

The title compound was prepared from the product of example 89, usingthe same method as that described for example 101, in 52% yield.

¹HNMR (400 MHz, CDCl₃) δ: 1.01 (t, 3H), 1.63 (s, 6H), 1.92 (s, 3H), 2.44(q, 2H), 3.72 (m, 2H), 3.86 (m, 2H), 4.46 (d, 2H), 6.47 (s, 1H), 6.58(d, 1H), 6.90-7.36 (m, 13H), 7.41 (d, 1H), 7.49 (d, 1H), 7.49 (t, 1H),7.64 (s, 1H), 8.03 (s, 1H); LRMS APCI m/z 695 [M+H]⁺

Example 103N-[2-({3-[2-(2-Hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]-N′-[3-[1-methyl-1-(methylthio)ethyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea

The title compound was prepared from the product of preparation 172,using a similar method to that described for example 101, in 34% yield.

¹HNMR (400 MHz, CDCl₃) δ: 1.57 (s, 6H), 1.89 (s, 3H), 2.34 (q, 2H), 3.52(m, 2H), 4.06 (m, 2H), 4.36 (d, 2H), 4.70 (m, 1H), 6.33 (s, 1H), 6.99(m, 1H), 7.10-7.34 (m, 11H), 7.58 (m, 2H), 7.81 (d, 1H), 8.10 (s, 1H),8.25 (s, 1H); LRMS APCI m/z 681 [M+H]⁺

Example 104N-{3-tert-Butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-ethylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

A solution of the product of preparation 204 (360 mg, 1 mmol) indimethylsulfoxide (5 mL) was added to a solution of the product ofpreparation 116 (490 mg, 1 mmol) and the mixture was stirred at roomtemperature for 18 hours and at 50° C. for 3 hours. The reaction mixturewas then cooled to room temperature, diluted with dichloromethane (10mL) and washed with 1M hydrochloric acid (1 mL), water (10 mL), 1Msodium hydroxide (10 mL) and brine (10 mL). The organic solution wasdried over magnesium sulfate and concentrated in vacuo. The residue wasdissolved in methanol (5 mL), para-toluenesulfonic acid (100 mg) wasadded and the mixture was stirred at room temperature for 18 hours. Thereaction mixture was then concentrated in vacuo and the residue wasdissolved in dichloromethane (30 mL) and washed with water (2×10 mL).The organic solution was dried over magnesium sulfate, concentrated invacuo and the residue was purified by column chromatography on silicagel, eluting with ethyl acetate:methanol, 95:5, to afford the titlecompound in 31% yield, 208.3 mg.

¹HNMR (400 MHz, CDCl₃) δ: 1.07 (t, 3H), 1.31 (s, 9H), 2.52 (q, 2H), 3.84(t, 2H), 4.01 (t, 2H), 4.53 (d, 2H), 6.13 (brs, 1H), 6.33 (s, 1H), 6.75(d, 1H), 7.01 (m, 3H), 7.21 (m, 3H), 7.26 (m, 3H), 7.36 (m, 3H), 7.45(d, 1H), 7.52 (m, 1H), 7.57 (d, 1H), 7.71 (s, 1H); LRMS APCI m/z 662[M+H]⁺

Example 105N-{3-tert-Butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the products of preparations 116and 206, using the same method as that described for example 104, as asolid in 36% yield.

¹HNMR (400 MHz, CDCl₃) δ: 1.31 (s, 9H), 2.21 (s, 3H), 3.83 (m, 2H), 3.98(m, 2H), 4.53 (d, 2H), 6.18 (brs, 1H), 6.33 (s, 1H), 6.72 (d, 1H), 7.00(m, 3H), 7.09 (brs, 1H), 7.20 (m, 3H), 7.35 (m, 6H), 7.45 (d, 1H), 7.52(d, 1H), 7.71 (s, 1H); LRMS APCI m/z 648 [M+H]⁺

Example 106N-{3-tert-Butyl-1-[4-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

Tetraethylammonium fluoride dihydrate (60 mg, 0.40 mmol) was added to asolution of the product of preparation 136 (200 mg, 0.29 mmol) intetrahydrofuran (5 mL) and the mixture was stirred at room temperaturefor 6 hours. Further tetraethylammonium fluoride dihydrate (60 mg, 0.32mmol) was then added and the mixture was stirred at room temperature for48 hours. The reaction mixture was concentrated in vacuo and the residuewas partitioned between 1M hydrochloric acid (20 mL) and dichloromethane(20 mL). The aqueous layer was separated and extracted withdichloromethane (5×20 mL), and the combined organic solution was driedover sodium sulfate and concentrated in vacuo. Purification of theresidue by column chromatography on silica gel, eluting withdichloromethane:methanol, 99:1 to 92.5:7.5, followed by trituration withdichloromethane/diethyl ether, afforded the title compound as a solid in41% yield, 68.8 mg.

¹HNMR (300 MHz, CDCl₃) δ: 1.27 (s, 9H), 1.29 (d, 6H), 3.18 (m, 1H), 4.33(s, 2H), 4.46 (d, 2H), 4.69 (brs, 1H), 6.30 (s, 1H), 6.87 (d, 1H), 6.95(d, 2H), 7.07-7.25 (m, 7H), 7.36 (d, 1H), 7.74 (s, 1H), 8.04 (s, 1H);LCMS m/z 570 [M+H]⁺

Example 107N-{1-(3-Hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared from the product of preparation 227,using a similar method as that described for example 106, as a whitesolid in 65% yield.)

¹HNMR (400 MHz, DMSO-d₆) δ: 1.58 (s, 6H), 1.89 (s, 3H), 3.69 (s, 3H),4.38 (d, 2H), 6.32 (s, 1H), 6.77 (dd, 1H), 6.86 (m, 2H), 7.05 (m, 1H),7.22 (m, 8H), 7.56 (m, 2H), 7.84 (m, 2H), 8.32 (s, 1H), 9.77 (s, 1H);LCMS m/z 652 [M+H]⁺

Example 108N-[3-tert-Butyl-1-(3-hydroxy-4-methylphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

Tetraethylammonium fluoride dihydrate (2.78 g, 15.0 mmol) was added to asolution of the product of preparation 137 (951 mg, 1.39 mmol) intetrahydrofuran (10 mL) and the mixture was stirred at room temperaturefor 5 minutes. The reaction mixture was then concentrated in vacuo andthe residue was partitioned between 1M hydrochloric acid (25 mL) anddichloromethane (25 mL). The organic layer was separated, dried oversodium sulfate and concentrated in vacuo. Purification of the residue bycolumn chromatography on silica gel, eluting withdichloromethane:methanol, 95:5 to 90:10, followed by trituration withdichloromethane/methanol:diethyl ether, afforded the title compound as asolid in 11% yield, 83.7 mg.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.24 (s, 9H), 1.37 (d, 6H), 2.15 (s, 3H),3.38 (m, 1H), 4.42 (d, 2H), 6.19 (s, 1H), 6.74 (d, 1H), 6.89 (s, 1H),7.10-7.13 (m, 2H), 7.25-7.33 (m, 4H), 7.47 (m, 1H), 7.88 (m, 2H), 8.30(s, 1H), 8.80 (s, 1H); LCMS m/z 570.6 [M+H]⁺

Example 109N-(2-{[3-(2-Fluorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-(4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

The title compound was prepared from the product of preparation 163,using a similar method as that described for example 108, as a whitesolid in 26% yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.56 (s, 6H), 1.88 (s, 3H), 4.36 (d, 2H),6.30 (s, 1H), 6.83 (d, 2H), 7.00 (m, 1H), 7.23 (m, 7H), 7.44 (m, 2H),7.66 (m, 1H), 7.77 (m, 1H), 7.86 (d, 1H), 8.16 (d, 2H), 9.72 (s, 1H);LCMS m/z 640 [M+H]⁺

Example 110N-{1-(3-Hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea

The title compound was prepared from the product of preparation 225,using a similar method as that described for example 108, as a whitesolid in 53% yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.24 (s, 9H), 1.38 (d, 6H), 3.58 (m, 1H),4.41 (d, 2H), 6.23 (s, 1H), 6.74 (m, 1H), 6.87 (m, 2H), 7.01-7.17 (m,2H), 7.20-7.29 (m, 5H), 7.67 (m, 1H), 8.28 (m, 1H), 8.58 (m, 1H), 9.72(s, 1H); LCMS m/z 632.6 [M+H]⁺

Example 111N-(2-{[3-(2-Fluorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-(3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea

The title compound was prepared from the product of preparation 226,using a similar method as that described for example 108, as a whitesolid in 53% yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.57 (s, 6H), 1.89 (s, 3H), 4.38 (d, 2H),6.32 (s, 1H), 6.78 (dd, 1H), 6.86 (m, 2H), 7.05 (m, 1H), 7.28 (m, 6H),7.44 (m, 2H), 7.67 (m, 1H), 7.77 (m, 1H), 7.87 (d, 1H), 8.20 (m, 1H),8.31 (s, 1H), 9.77 (s, 1H); LCMS m/z 640 [M+H]⁺

Example 112N-[3-(1,1-Dimethylpropyl)-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

The title compound was prepared form the product of preparation 243,using a similar method as that described for example 108, as a whitesolid in 31% yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 0.75 (t, 3H), 1.19 (s, 6H), 1.57 (q, 2H),2.40 (s, 3H), 4.38 (d, 2H), 6.20 (s, 1H), 6.76 (d, 1H), 6.87 (m, 2H),7.03 (m, 1H), 7.24-7.37 (m, 6H), 7.55 (m, 2H), 7.61 (m, 1H), 7.85-7.92(m, 2H), 8.30 (m, 2H), 9.77 (s, 1H); LCMS m/z 650 [M+H]⁺

Example 113N-[3-tert-Butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-fluorophenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

The title compound was prepared form the product of preparation 248,using the same method as that described for the preparation of example108, as a white solid in 95% yield.

¹HNMR (300 MHz, DMSO-d₆) δ 1.23 (s, 9H), 4.37 (d, 2H), 6.14 (s, 1H),6.85 (d, 2H), 7.18-7.30 (m, 8H), 7.39-7.49 (m, 2H), 7.68 (m, 1H),7.76-7.87 (m, 2H), 8.19 (s, 1H), 8.38 (s, 1H), 9.87 (s, 1H); LCMS m/z608 [M+H]⁺

Example 114N-[3-tert-Butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[4-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea

The title compound was prepared form the product of preparation 253,using the same method as that described for the preparation of example97, as a pale yellow solid in 78% yield.

¹HNMR (400 MHz, DMSO-d₆) δ: 1.21 (s, 9H), 2.53 (s, 3H), 4.40 (d, 2H),6.21 (s, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 6.88 (s, 1H), 7.02 (m, 1H),7.20 (d, 1H), 7.25 (m, 2H), 7.31 (m, 3H), 7.43 (d, 2H), 7.81 (d, 2H),7.83 (d, 1H), 8.27 (s, 1H), 8.37 (s, 1H), 9.73 (s, 1H); LRMS APCI m/z636 [M+H]⁺

Example 115N-{1-[3-(2-Hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-isopropylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

para-Toluenesulfonic acid (63 mg, 3.3 mmol) was added to a solution ofthe product of preparation 255 (262 mg, 3.3 mmol) in methanol (15 mL)and the mixture was stirred at room temperature for 72 hours. Thereaction mixture was then diluted with water, basified with sodiumhydrogen carbonate solution and the resulting precipitate was filteredoff to afford the title compound as a white solid in 76% yield.

¹HNMR (300 MHz, DMSO-d₆) δ: 1.09 (d, 6H), 1.57 (s, 6H), 1.89 (s, 3H),2.75 (m, 1H), 3.69 (s, 2H), 4.40 (d, 2H), 4.34 (d, 2H), 4.88 (brs, 1H),6.31 (s, 1H), 6.93 (dd, 1H), 7.03 (m, 2H), 7.26 (m, 8H), 7.46 (d, 1H),7.56 (d, 2H), 7.83 (d, 2H), 8.63 (s, 1H); LCMS m/z 708 [M+H]⁺

The following compounds have been prepared by analogy with the methodspreviously described.

Example LCMS m/z No. Definitions [M + H]⁺ 116 A = C(CH₃)₃; X = 4-CH₃;694.6 R³ = 2-benzyloxyphenyl 117 A = (CH₃S)C(CH₃)₂; X = 3-CF₃; 640 R³ =CH(CH₃)₂ 118 A = C(CH₃)₃; X = 4-C(O)NHCH₃; 597.2747^(A) R³ = CH(CH₃)₂119 A = C(CH₃)₃; X = 3-F, 4-F; 674.6 R³ = 2-chloro-3-methoxyphenyl 120 A= C(CH₃)₃; X = 3-Cl, 4-Cl; 748 R³ = 2-benzyloxyphenyl 121 A = C(CH₃)₃; X= 3-CN; 705 R³ = 2-benzyloxyphenyl 122 A = C(CH₃)₃; X = 4-CN; 705 R³ =2-benzyloxyphenyl 123 A = C(CH₃)₃; X = 3-F; 698 R³ = 2-benzyloxyphenyl124 A = C(CH₃)₃; X = 3-benzyloxy, 660.6 5-CH₃; R³ = CH(CH₃)₂ 125 A =(CH₃S)C(CH₃)₂; X = 4-(2- 632 hydroxyethoxy); R³ = CH(CH₃)₂ 126 A =(CH₃S)C(CH₃)₂; X = 4-Br; 652 R³ = CH(CH₃)₂ 127 A = (CH₃S)C(CH₃)₂; X =3-Br; 652 R³ = CH(CH₃)₂ 128 A = C(CH₃)₃; X = 3-F, 4-F; 660.5 R³ =2-chloro-3-hydroxyphenyl; 129 A = C(CH₃)₃; X = 3-CH₃CH₂, 598.6 4-OCH₃;R³ = CH(CH₃)₂ 130 A = C(CH₃)₃; X = 3-OCH₃, 598.6 4-CH₃CH₂; R³ = CH(CH₃)₂131 A = C(CH₃)₃; X = 3-OH, 5-CH₃CH₂; 584.6 R³ = CH(CH₃)₂ 132 A =(CH₃S)C(CH₃)₂; X = 4-OH; 650.2364^(A) R³ = 2-ethylphenyl; 133 A =(CH₃S)C(CH₃)₂; X = 4-OH; 588 R³ = CH(CH₃)₂ 134 A = (CH₃S)C(CH₃)₂; X =4-Br; 700 R³ = 2-hydroxyphenyl 135 A = C(CH₃)₃; X = 3-OCH₃, 4-Cl; 604.6R³ = CH(CH₃)₂ 136 A = (CH₃S)C(CH₃)₂; X = 3-CH₃, 600 5-CH₃; R³ = CH(CH₃)₂137 A = (CH₃S)C(CH₃)₂; 600 X = 4-CH₂CH₃; R³ = CH(CH₃)₂ 138 A = C(CH₃)₃;X = 4-(2-hydroxyethoxy); 664.5 R³ = 2-methoxyphenyl 139 A = C(CH₃)₃; X =4-(2-hydroxyethoxy); 676.6 R³ = 2-isopropylphenyl 140 A = (CH₃S)C(CH₃)₂;X = 4-OH; 652.6 R³ = 2-methoxyphenyl 141 A = C(CH₃)₃; X =4-(2-hydroxyethoxy); 652.6 R³ = 2-fluorophenyl 142 A = (CH₃S)C(CH₃)₂; X= 4-OH; 664.6 R³ = 2-isopropylphenyl 143 A = C(CH₃)₃; X = 4-OH; 620.6 R³= 2-methoxyphenyl 144 A = C(CH₃)₃; X = 4-OH; 632.6 R³ =2-isopropylphenyl 145 A = C(CH₃)₃; X = 3-OH; 620.6 R³ = 2-methoxyphenyl146 A = (CH₃S)C(CH₃)₂; X = 4- 684.4 (2-hydroxyethoxy); R³ =2-fluorophenyl 147 A = (CH₃S)C(CH₃)₂; X = 4-(2- 696.5 hydroxyethoxy); R³= 2-methoxy-phenyl 148 A = C(CH₃)₃; X = 3-OH; 608.6 R³ = 2-fluorophenyl149 A = (CH₃S)C(CH₃)₂; X = 4-(2- 708.6 hydroxyethoxy); R³ =2-isopropyl-phenyl 150 A = (CH₃S)C(CH₃)₂; X = 3-OH; 664.6 R³ =2-isopropylphenyl 151 A = (CH₃S)C(CH₃)₂; X = 3-CH₃; 650 R³ =2-hydroxy-4-methylphenyl 152 A = (CH₃S)C(CH₃)₂; X = 3-CH₃; 669^(B) R³ =2-hydroxy-3-chlorophenyl 153 A = (CH₃S)C(CH₃)₂; X = 4-CH₃; MicroanalysisR³ = 2-hydroxy-3-chlorophenyl found: C, 60.69; H, 4.82; N, 14.27.C₃₄H₃₂ClN₇O₂S₂ requires C, 60.93; H, 4.81; N, 14.63%. 154 A =(CH₃CH₂)C(CH₃)₂; X = H; 604.6 R³ = 2-hydroxyphenyl 155 A =(CH₃S)C(CH₃)₂; X = 4-CH₃; 650 R³ = 2-hydroxy-4-methylphenyl 156 A =C(CH₃)₃; X = 4-F; 622 R³ = 2-hydroxy-4-methylphenyl 157 A = C(CH₃)₃; X =3-F; 622 R³ = 2-hydroxy-4-methylphenyl 158 A = (CH₃CH₂)C(CH₃)₂; X =3-Cl; 570.6 R³ = CH(CH₃)₂ 159 A = C(CH₃)₃; X = 4-OH; 624 R³ =2-chlorophenyl 160 A = C(CH₃)₃; X = 3-(2-hydroxyethoxy); 600 R³ =CH(CH₃)₂ 161 A = C(CH₃)₃; X = 3-CH₃; 638, 640 R³ =3-chloro-2-hydroxyphenyl 162 A = (CH₃CH₂)C(CH₃)₂; X = 3-Cl, 604.6 4-OH;R³ = CH(CH₃)₂ 163 A = (CH₃CH₂)C(CH₃)₂; X = 3-F; 622.6 R³ =2-hydroxyphenyl 164 A = (CH₃S)C(CH₃)₂; X = 4-OH; 656 R³ = 2-chlorophenyl165 A = (CH₃S)C(CH₃)₂; X = 4-CH₃; 637 R³ = 2-hydroxyphenyl 166 A =(CH₃SCH₂)C(CH₃)₂; X = 3-CH₃; 650 R³ = 2-hydroxyphenyl 167 A = C(CH₃)₃; X= 3-CH₃; 604 R³ = 2-hydroxyphenyl 168 A = C(CH₃)₃; X = 4-OH; 606 R³ =2-hydroxyphenyl 169 A = C(CH₃)₃; X = H; 616 R³ = 4-carboxyphenyl 170 A =C(CH₃)₃; X = 4-CH₃; 656.1997^(A) R³ = 3-chloro-5-fluoro-2-hydroxyphenyl171 A = (CH₃SCH₂)C(CH₃)₂; X = 3-CN; 661 R³ = 2-hydroxyphenyl 172 A =(CH₃SCH₂)C(CH₃)₂; X = 4-CN; 661 R³ = 2-hydroxyphenyl 173 A = C(CH₃)₃; X= 4-OH; 650 R³ = 3-(2-hydroxyethoxy)phenyl 174 A = C(CH₃)₃; X = 4-CH₃;656 R³ = 3-chloro-5-fluoro-4-hydroxyphenyl 175 A = C(CH₃)₃; X =3-carboxymethoxy; 614 R³ = CH(CH₃)₂ 176 A = (CH₃S)C(CH₃)₂; X = 3-(2- 634hydroxyethoxy); R³ = 2-hydroxyphenyl 177 A = (CH₃S)C(CH₃)₂; X = 4-CH₃;650 R³ = 2-hydroxy-6-methylphenyl 178 A = (CH₃S)C(CH₃)₂; X = 4-OH;682.2252^(A) R³ = 3-(2-hydroxyethoxy)phenyl 179 A = C(CH₃)₃; X = 3-OH;666 R³ = 2-[(2-hydroxyethyl)thio]phenyl ^(A) = HRMS: m/z ^(B) = LRMS:m/z [M − H]⁻

LCMS Example m/z No. Definitions [M + H]⁺ 180 A = C(CH₃)₃; R² =pyridin-2-yl; R³ = CH(CH₃)₂ 541 181 A = C(CH₃)₃; R² = isoquinolin-5-yl;591.6 R³ = CH(CH₃)₂ 182 A = (CH₃CH₂)C(CH₃)₂; R² = pyridin-3-yl; 605.6 R³= 2-hydroxyphenyl 183 A = C(CH₃)₃; R² = isoquinolin-7-yl; 591.2 R³ =CH(CH₃)₂

The following compounds in list² may be prepared by analogy with themethods previously described. In another embodiment of the invention, apreferred group of compounds is that in which each substituent is asspecified in the list² below.

Preferably, the compound of formula (I) is selected from the list²:

-   N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[3-tert-butyl-1-{3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-(2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[3-tert-butyl-1-(4-chloro-3-hydroxyphenyl)-1H-pyrazole-5-yl]-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(3-chloro-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1,1-dimethyl-2-<methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(4-chloro-3-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[1-(4-chloro-3-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(4-chloro-3-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(4-chloro-3-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(4-chloro-3-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(4-chloro-3-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[1-(4-chloro-3-hydroxyphenyl)-3-<1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[3-tert-butyl-1-(3-cyano-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazole-5-yl}-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{1-(3-cyano-4-hydroxyphenyl)-3-[1,1-dimethyl-2-(methylthio)ethyl]-1H-pyrazol-5-yl}-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[3-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[4-(2-hydroxyethoxy)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-[2-({3-[2-(methylthio)phenyl][1,2,4]triazolo[4,3-a]pyridin-6-yl}thio)benzyl]urea-   N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-{2-[(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-[1-(3-cyano-4-hydroxyphenyl)-3-(1,1-dimethylpropyl)-1H-pyrazol-5-yl]-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea-   N-{3-tert-butyl-1-[3-<2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea-   N-{3-tert-butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea-   N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea-   N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea-   N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-[3-(2-hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-[3-(2-hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-[4-(2-hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-[4-(2-hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1,1-dimethyl-2-(methylthio)ethyl]-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1,1-dimethyl-2-(methylthio)ethyl]-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1,1-dimethyl-2-(methylthio)ethyl]-1-[4-(2-hydroxyethoxy)phenyl)]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1,1-dimethyl-2-(methylthio)ethyl]-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-(1,1-dimethylpropyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-(1,1-dimethylpropyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(5-chloro-2-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-(1,1-dimethylpropyl)-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(2-chloro-5-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-(1,1-dimethylpropyl)-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-{3-tert-butyl-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea-   N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea-   N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-[3-(2-hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{1-[4-(2-hydroxyethoxy)phenyl]-3-[1-methyl-1-(methylthio)ethyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1,1-dimethyl-2-(methylthio)ethyl]-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-[1,1-dimethyl-2-(methylthio)ethyl]-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-(1,1-dimethylpropyl)-1-[3-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-(2-{[3-(3-cyano-4-hydroxyphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)-N′-{3-(1,1-dimethylpropyl)-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}urea-   N-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-(2-{[3-(2-ethylphenyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]thio}benzyl)urea

1. A method of treating a disease, disorder or condition in a mammal,said method comprising administering to said mammal a therapeuticallyeffective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is CH₃, SCH₃,SCH₂CH₃, CH₂CH₃, H or CH₂SCH₃; R^(1a) is CH₃ or CH₂CH₃; R² isheteroaryl, heterocyclyl, aryl, or carbocyclyl; R³ is heteroaryl,heterocyclyl, aryl, carbocyclyl or R⁷; R⁷ is (C₁-C₆)alkyl optionallysubstituted with one to three substituents independently selected fromOH, halo, NR⁵R⁶, (C₁-C₆)alkoxy, —S(O)_(p)(C₁-C₆)alkyl, CO₂H, CONR⁵R⁶,heteroaryl, heterocyclyl, aryl, carbocyclyl, aryloxy, carbocyclyloxy,heteroaryloxy and heterocyclyloxy; p is 0, 1 or 2; R⁵ and R⁶ are takenseparately and are each independently selected from H and (C₁-C₄)alkyl,said (C₁-C₄)alkyl being optionally substituted with one to threesubstituents independently selected from OH and halo, or R⁵ and R⁶ aretaken together with the nitrogen to which they are attached to form apiperazinyl, piperidinyl, morpholinyl or pyrrolidinyl group, whereinsaid piperazinyl, piperidinyl, morpholinyl and pyrrolidinyl groups areeach optionally substituted by one to three OH); said aryl isindependently phenyl or naphthyl, said phenyl or naphthyl beingoptionally substituted with one to three substituents independentlyselected from halo, —CN, —CO₂H, OH, CONR⁵R⁶, NR⁵R⁶, R⁸ and R⁹; R⁸ isindependently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,—CO₂(C₁-C₆)alkyl, —S(O)_(p)(C₁-C₆)alkyl, —CO(C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, wherein each R⁸ is optionally substitutedindependently with one to three substituents independently selectedfrom: (C₁-C₆)alkoxy, optionally substituted with one to threesubstituents independently selected from OH, halo, CO₂H, CONR⁵R⁶ andNR⁵R⁶, —S(O)_(p)(C₁-C₆)alkyl, optionally substituted with one to threesubstituents independently selected from OH, halo, CO₂H, CONR⁵R⁶ andNR⁵R⁶, OH, halo, NR⁵R⁶, CO₂H, CONR⁵R⁶, and R⁹; R⁹ is heteroaryl²,heterocyclyl², aryl², carbocyclyl², aryl²oxy, carbocyclyl²oxy,heteroaryl²oxy or heterocyclyl²oxy; aryl² is phenyl or naphthyl whereinsaid phenyl or naphthyl in the definition of aryl² is optionallysubstituted with one to three substituents independently selected fromhalo, —CN, —CO₂H, OH, and CONR⁵R⁶; carbocyclyl is a monocyclic orbicyclic, saturated or partially unsaturated ring system comprising from3 to 10 ring carbon atoms, wherein said ring system is optionallysubstituted with one to three substituents independently selected fromhalo, —CN, —CO₂H, OH, CONR⁵R⁶, R⁸ and R⁹; carbocyclyl² is a monocyclicor bicyclic, saturated or partially unsaturated ring system comprisingfrom 3 to 10 ring carbon atoms, optionally substituted with one to threesubstituents independently selected from halo, —CN, —CO₂H, —OH andCONR⁵R⁶; heterocyclyl and heterocyclyl² are each independently a 3- to10-membered, saturated or partially unsaturated, monocyclic or bicyclicgroup comprising from 1 to 4 ring heteroatoms independently selectedfrom N, O, and S; heteroaryl and heteroaryl² are each independently a 5-to 10-membered, monocyclic or bicyclic aromatic group comprising from 1to 4 ring heteroatoms independently selected from N, O, and S, providedthat the total number of ring S atoms does not exceed 1, and the totalnumber of ring O atoms does not exceed 1; each heterocyclyl andheteroaryl group is, independently, optionally substituted on one tothree ring carbon atoms with one to three substituents independentlyselected from halo, —CN, —CO₂H, OH, CONR⁵R⁶, R⁸ and R⁹, andindependently optionally substituted on one to three ring nitrogen atomswith one to three substituents independently selected from H and(C₁-C₆)alkyl; and each heterocyclyl² and heteroaryl² group is,independently, optionally substituted on one to three ring carbon atomswith one to three substituents independently selected from halo, —CN,—CO₂H, OH and CONR⁵R⁶, and independently optionally substituted on oneto three ring nitrogen atoms with one substituent independently selectedfrom H and (C₁-C₆)alkyl, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable diluent, carrier or adjuvant, wherein said disease, disorderor condition is selected from the group consisting of asthma, chronic oracute bronchoconstriction, small airways obstruction, emphysema, chronicobstructive pulmonary disease (COPD), bronchitis, bronchiectasis andCOPD that includes chronic bronchitis.
 2. A method of claim 1 whereinsaid asthma is selected from the group consisting of atopic asthma,non-atopic asthma, allergic asthma, atopic bronchial IgE-mediatedasthma, bronchial asthma, essential asthma, true asthma, intrinsicasthma caused by pathophysiologic disturbances, extrinsic asthma causedby environmental factors, essential asthma of unknown or inapparentcause, non-atopic asthma, bronchitic asthma, emphysematous asthma,exercise-induced asthma, allergen induced asthma, cold air inducedasthma, occupational asthma, infective asthma caused by bacterial,fungal, protozoal, or viral infection, non-allergic asthma, incipientasthma, wheezy infant syndrome and bronchiolytis; said bronchitis isselected from the group consisting of acute bronchitis, acutelaryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis,croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis,productive bronchitis, staphylococcus or streptococcal bronchitis andvesicular bronchitis; and said bronchiectasis is selected from the groupconsisting of cylindric bronchiectasis, sacculated bronchiectasis,fusiform bronchiectasis, capillary bronchiectasis, cysticbronchiectasis, dry bronchiectasis and follicular bronchiectasis.
 3. Amethod of claim 1 wherein said disease, disorder or condition isselected from asthma and chronic obstructive pulmonary disease (COPD).4. A method of treating a disease, disorder or condition in a mammal,said method comprising administering to said mammal a therapeuticallyeffective amount ofN-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a therapeutically effective amount ofN-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N′-{2-[(3-{2-[(2-hydroxyethyl)thio]phenyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)thio]benzyl}urea,or a pharmaceutically acceptable salt of thereof, and a pharmaceuticallyacceptable diluent, carrier or adjuvant, wherein said disease, disorderor condition is selected from the group consisting of asthma, chronic oracute bronchoconstriction, small airways obstruction, emphysema, chronicobstructive pulmonary disease (COPD), bronchitis, bronchiectasis andCOPD that includes chronic bronchitis.
 5. A method of claim 4 whereinsaid asthma is selected from the group consisting of atopic asthma,non-atopic asthma, allergic asthma, atopic bronchial IgE-mediatedasthma, bronchial asthma, essential asthma, true asthma, intrinsicasthma caused by pathophysiologic disturbances, extrinsic asthma causedby environmental factors, essential asthma of unknown or inapparentcause, non-atopic asthma, bronchitic asthma, emphysematous asthma,exercise-induced asthma, allergen induced asthma, cold air inducedasthma, occupational asthma, infective asthma caused by bacterial,fungal, protozoal, or viral infection, non-allergic asthma, incipientasthma, wheezy infant syndrome and bronchiolytis; said bronchitis isselected from the group consisting of acute bronchitis, acutelaryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis,croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis,productive bronchitis, staphylococcus or streptococcal bronchitis andvesicular bronchitis; and said bronchiectasis is selected from the groupconsisting of cylindric bronchiectasis, sacculated bronchiectasis,fusiform bronchiectasis, capillary bronchiectasis, cysticbronchiectasis, dry bronchiectasis and follicular bronchiectasis.
 6. Amethod of claim 4 wherein said disease, disorder or condition isselected from asthma and chronic obstructive pulmonary disease (COPD).